Bioavailability and Bioequivalence: Definitions of different parameters relative to bioavailability, purpose of bioavailability, relative and absolute to bioavailability, methods of assaying bioavailabilty, criteria for bioequivalence studies, method and determination of bioavailability.
Powders are mixtures of finely divided drugs and chemicals that can be used internally or externally. Powders consist of particles that can range in size from 10 mm to 1 μm. The particle size distribution and properties influence how powders can be used. Before using powders to make pharmaceutical products, their chemical and physical characteristics like morphology, purity, solubility, and stability are analyzed. Proper blending and avoiding segregation of powder mixtures is important for ensuring uniform and consistent dosing.
This document discusses pharmaceutical creams. It defines what a cream is and describes the anatomy of skin. It outlines different types of creams including cleansing, vanishing, foundation, night, massage, hand, body, and all-purpose creams. It discusses the components and manufacturing processes of creams and provides examples of formulations. Finally, it covers the uses of creams and some novel advances in cream technology.
This document defines tablet diluents and describes the properties and purposes of common diluents lactose and calcium phosphate. It states that diluents are used to increase tablet bulk and weight while allowing direct compression manufacturing. Key properties of diluents include being inert, non-toxic, and not affecting drug bioavailability. Common diluents are classified as organic like lactose or inorganic like calcium phosphate. Lactose is the most widely used diluent and comes in several forms with different properties for tableting. Calcium phosphate and tribasic calcium phosphate are also described as inexpensive inorganic diluents.
This presentation summarizes various dissolution testing apparatus. It describes 7 types of apparatus recognized by USP, IP, BP and EP. The first four apparatus are commonly used and include the rotating basket, paddle, reciprocating cylinder and flow through cell. The presentation provides details on the design, working, and typical uses of each apparatus type. It also discusses commonly used dissolution media and concludes that the goal of dissolution testing is to ensure pharmaceutical quality and understand biopharmaceutical properties like rate and extent of drug absorption.
This document provides an overview of pharmaceutical product development. It discusses the objectives of product development which include designing quality products and manufacturing processes to consistently deliver intended performance. It also covers regulations related to preformulation, formulation development, stability assessment, and quality control testing of different dosage forms. The document outlines guidelines from organizations like ICH and WHO for various stages of product development.
This document provides an overview of semi-solid dosage forms such as ointments, creams, pastes, and gels. It discusses their ideal properties and examples. It also describes the basic introduction, ingredients used in preparation including bases, preservatives, emulsifiers, and gelling agents. Methods of preparation like trituration, fusion, and emulsification are covered. The preparation of oil and aqueous phases and mixing of phases is explained. Finally, the document discusses the storage conditions and references for semi-solid dosage forms.
Cold creams are oil-in-water emulsions used to smooth skin and remove makeup. They produce a cooling effect due to the slow evaporation of water. Common ingredients include beeswax, mineral oils, and scents. Cold creams were traditionally made from animal fats but now use vegetable and mineral oils. When applied, the emulsion inverts from oil-in-water to water-in-oil. Cleansing creams are similar but contain detergents to clean the skin by removing dirt, oil, and dead cells in addition to makeup. Vanishing creams are oil-in-water emulsions that leave a thin, almost invisible layer of stearic acid on the skin.
Powders are mixtures of finely divided drugs and chemicals that can be used internally or externally. Powders consist of particles that can range in size from 10 mm to 1 μm. The particle size distribution and properties influence how powders can be used. Before using powders to make pharmaceutical products, their chemical and physical characteristics like morphology, purity, solubility, and stability are analyzed. Proper blending and avoiding segregation of powder mixtures is important for ensuring uniform and consistent dosing.
This document discusses pharmaceutical creams. It defines what a cream is and describes the anatomy of skin. It outlines different types of creams including cleansing, vanishing, foundation, night, massage, hand, body, and all-purpose creams. It discusses the components and manufacturing processes of creams and provides examples of formulations. Finally, it covers the uses of creams and some novel advances in cream technology.
This document defines tablet diluents and describes the properties and purposes of common diluents lactose and calcium phosphate. It states that diluents are used to increase tablet bulk and weight while allowing direct compression manufacturing. Key properties of diluents include being inert, non-toxic, and not affecting drug bioavailability. Common diluents are classified as organic like lactose or inorganic like calcium phosphate. Lactose is the most widely used diluent and comes in several forms with different properties for tableting. Calcium phosphate and tribasic calcium phosphate are also described as inexpensive inorganic diluents.
This presentation summarizes various dissolution testing apparatus. It describes 7 types of apparatus recognized by USP, IP, BP and EP. The first four apparatus are commonly used and include the rotating basket, paddle, reciprocating cylinder and flow through cell. The presentation provides details on the design, working, and typical uses of each apparatus type. It also discusses commonly used dissolution media and concludes that the goal of dissolution testing is to ensure pharmaceutical quality and understand biopharmaceutical properties like rate and extent of drug absorption.
This document provides an overview of pharmaceutical product development. It discusses the objectives of product development which include designing quality products and manufacturing processes to consistently deliver intended performance. It also covers regulations related to preformulation, formulation development, stability assessment, and quality control testing of different dosage forms. The document outlines guidelines from organizations like ICH and WHO for various stages of product development.
This document provides an overview of semi-solid dosage forms such as ointments, creams, pastes, and gels. It discusses their ideal properties and examples. It also describes the basic introduction, ingredients used in preparation including bases, preservatives, emulsifiers, and gelling agents. Methods of preparation like trituration, fusion, and emulsification are covered. The preparation of oil and aqueous phases and mixing of phases is explained. Finally, the document discusses the storage conditions and references for semi-solid dosage forms.
Cold creams are oil-in-water emulsions used to smooth skin and remove makeup. They produce a cooling effect due to the slow evaporation of water. Common ingredients include beeswax, mineral oils, and scents. Cold creams were traditionally made from animal fats but now use vegetable and mineral oils. When applied, the emulsion inverts from oil-in-water to water-in-oil. Cleansing creams are similar but contain detergents to clean the skin by removing dirt, oil, and dead cells in addition to makeup. Vanishing creams are oil-in-water emulsions that leave a thin, almost invisible layer of stearic acid on the skin.
This document provides information on creams as a semisolid dosage form. It begins by defining creams and describing the two main types: oil-in-water (O/W) and water-in-oil (W/O) emulsions. The uses and manufacturing process of creams are then outlined. The document also includes details on specific types of creams, formulations, quality control testing using vertical diffusion cell methods, and concludes with a case study example of a betamethasone cream.
This document provides an overview of the formulation and development of parenteral products. It discusses the key components including containers, closures, processing, formulation, production facilities, and evaluation methods. The production area is divided into five sections - cleanup, preparation, aseptic, quarantine, and finishing/packaging areas. Parenteral formulations contain active drugs, vehicles, and adjuvants. Finished products undergo sterility, clarity, leakage, pyrogen, and assay testing to ensure quality control.
This document provides an overview of mouth dissolving films as an innovative drug delivery system. It discusses the anatomy and physiology of the oral cavity, advantages and disadvantages of mouth dissolving films, and the role of saliva. It also covers formulation ingredients, preparation methods like solvent casting, and evaluation parameters for mouth dissolving films such as mechanical properties, disintegration time, and in vitro dissolution testing. The document aims to educate about this drug delivery system for pediatric and geriatric patients.
This document discusses the design and evaluation of bioequivalence studies. It defines bioequivalence as the absence of a significant difference in the rate and extent to which the active drug becomes available at the site of action when administered under similar conditions. The document discusses various study designs including crossover, replicate, and non-replicate designs. It also covers sampling, criteria for comparisons between test and reference products, and the roles of bioequivalence studies in drug review and approval processes.
The document discusses bioequivalence, which refers to two drug products having the same rate and extent of absorption. There are two types of bioequivalence testing: in vivo, which involves human subjects; and in vitro, which involves dissolution testing. In vivo testing is generally required for immediate-release oral drugs that are systemically absorbed, have a narrow therapeutic index, or have complicated absorption properties. In vitro dissolution testing may suffice in some cases, such as when only the drug strength differs between products or when an acceptable in vitro-in vivo correlation exists.
This document discusses quality control tests for topical preparations, including transdermal drug delivery systems (TDDS). It describes various types of topical preparations like creams, ointments, gels, pastes, and jellies. It also discusses the common ingredients in TDDS like drugs, liners, adhesives, permeation enhancers, backing layers, and polymer matrices. Finally, it outlines the key physicochemical tests performed for quality control of TDDS, including thickness, weight uniformity, drug content, content uniformity, moisture content, and moisture uptake testing.
This document discusses phytosomes, which are herbal extracts bound to phospholipids. Phytosomes have several advantages over traditional herbal extracts, including enhanced absorption and bioavailability. The document outlines the structure and properties of phytosomes, comparing them to liposomes. It also describes the preparation process, evaluation methods, and applications of various phytosome formulations. Common phytosomes include silymarin (milk thistle) for liver health, grape seed for antioxidants, green tea for antioxidants and chronic diseases, and curcumin for anti-inflammatory effects. Phytosomes allow herbal constituents to be absorbed more effectively and produce better results than conventional herbal extracts.
This document discusses various types of pharmaceutical excipients used in compounding dosage forms. It lists 16 important excipients including antioxidants, preservatives, acidifying agents, and alkalizing agents. Details are provided on the chemistry, physical properties and uses of some specific excipients including ascorbic acid, BHA, chlorobutanol, sodium bicarbonate and sodium carbonate. Excipients are added to drugs to provide suitable consistency or form and aid in compounding pharmaceutical products.
Cold cream , vanishing cream , IDEAL PROPERTIES OF VANISHING CREAMS , MAJOR INGREDIENTS USED FOR THE PRODUCTION OF VANISHING CREAMS , FORMULATION OF VANISHING CREAM , IDEAL CHARACTERISTICS OF COLD CREAM , INGREDIENTS USED FOR PREPARATION OF COLD CREAM , FORMULATION OF COLD CREAM
This document defines soft gelatin capsules and describes their anatomy, manufacturing process, quality considerations, and types. Soft gelatin capsules have a soft gelatin shell containing liquids, suspensions, or semisolids. The shell is made of gelatin, plasticizer, and water. The content can be liquids, solutions, or suspensions. The manufacturing process involves making the gel and content mixtures, encapsulating using machinery, drying, inspecting, and packaging. Quality is ensured through ingredient and in-process testing and finished product testing. Vegicaps are an alternative animal-free soft capsule with a seaweed and starch shell.
This document provides an introduction to bioequivalence studies, including definitions of key terms, the need for and importance of bioequivalence studies, criteria for establishing a bioequivalence requirement, types of bioequivalence studies, design of bioequivalence studies, evaluation of bioequivalence study results, and clinical significance. It discusses in vivo and in vitro bioequivalence study types and designs, including factors such as single dose, multiple dose, fasting, food effect, and crossover designs. Statistical evaluation methods including ANOVA, confidence intervals, and bioequivalence limits of 80-125% are also summarized.
The document discusses the manufacturing process of parenteral preparations. It describes parenterals as sterile liquids or solids for injection or implantation. The manufacturing process involves planning, material management, production, quality control testing, filling, and packaging. Production areas are divided into strict zones based on cleanliness. Environmental controls and facility design aim to prevent contamination, with areas for filling, weighing, storage, and administration. Personnel flow and utility locations are also considered for efficiency.
The document outlines the evaluation of various solid, semi-solid, and liquid dosage forms. For solid dosage forms like tablets, important tests include general appearance, weight variation, content uniformity, hardness, friability, disintegration, and dissolution. These tests are conducted to ensure quality, consistency in drug content between tablets, and that the drug will release and dissolve properly. Similar tests are described for other dosage forms like capsules, granules, powders, ointments, creams, suppositories, syrups, suspensions, emulsions, and novel delivery systems. The goal of evaluation is to quantify properties and assess interactions that impact drug stability and bioavailability.
Parenterals are formulated as solutions, suspensions, emulsions, powders, or nano systems. They contain an active ingredient, vehicle, and added substances to maintain stability and sterility. Added substances include solubilizers, antioxidants, chelating agents, antimicrobial preservatives, buffers, tonicity contributors, and protectants. Parenterals are formulated to be sterile and in stable forms like suspensions, solutions, emulsions or powders for reconstitution to facilitate easy administration while maintaining purity and therapeutic activity. They undergo quality testing for leakage, clarity, pyrogenicity and sterility.
This document discusses important considerations for dosage form design and pharmaceutical formulation. It covers topics like pharmaceutics, drug substance characteristics, excipient selection and functions, preformulation studies, stability testing, and packaging. Preformulation studies help determine appropriate dosage forms and ensure drug stability. Stability is enhanced by protecting drugs from moisture, oxygen, light and other degradation factors through packaging and formulation choices. Proper dosage form design and formulation are essential for producing effective and safe drug products.
This document discusses modified-release oral dosage forms, including extended-release and delayed-release forms. It describes various technologies used to modify drug release rates, such as coatings, matrices, and osmotic pumps. It also covers terminology, drug candidates suited for modified dosing, clinical considerations, and FDA/USP regulations regarding testing, labeling and in vitro-in vivo correlations. The goal of these dosage forms is to reduce dosing frequency while maintaining therapeutic drug levels over time.
The document discusses creams as a semisolid dosage form containing drug substances dispersed or dissolved in a suitable base. It defines oil-in-water and water-in-oil creams and provides examples of each. The key steps in cream preparation and various tests to characterize creams are described, including determining type of emulsion, viscosity, pH, globule size, stability, and spreadability. Creams offer advantages over other semisolid forms like being less greasy and more easily washed off.
Physicochemical Properties effect on Absorption of DrugsSuraj Choudhary
This document discusses factors affecting drug absorption from oral dosage forms. It covers physiological factors like gastric emptying time and pH, as well as physicochemical drug properties including solubility, dissolution rate, and polymorphism that influence drug absorption. Particle size and surface area are emphasized, with smaller particles increasing absorption for hydrophilic drugs but potentially decreasing it for hydrophobic drugs. The pH partition hypothesis and importance of drug stability are also summarized.
Pharmacokinetics / Biopharmaceutics - Bioavailability and BioequivalenceAreej Abu Hanieh
This document discusses bioavailability and bioequivalence. It defines key terms and describes how bioavailability is measured, including plasma drug concentration over time, urinary drug excretion, clinical studies, and in vitro dissolution testing. The document outlines the design of bioequivalence studies in humans and the statistical analysis used to determine if a generic drug is bioequivalent to the brand name version. It also discusses issues that can arise in bioequivalence testing.
This document discusses bioavailability and bioequivalence as it relates to drug products. It defines key terms like multisource drug products, single-source drug products, bioavailability, bioequivalence, relative bioavailability, and absolute bioavailability. It describes various methods that can be used to assess bioavailability, including pharmacokinetic methods like measuring plasma drug concentration over time and urinary excretion studies, as well as pharmacodynamic and in-vitro dissolution methods. The purpose of bioavailability studies is to ensure drug products are safe, effective, and therapeutically equivalent when generic versions enter the market after patents expire on brand name drugs.
This document provides information on creams as a semisolid dosage form. It begins by defining creams and describing the two main types: oil-in-water (O/W) and water-in-oil (W/O) emulsions. The uses and manufacturing process of creams are then outlined. The document also includes details on specific types of creams, formulations, quality control testing using vertical diffusion cell methods, and concludes with a case study example of a betamethasone cream.
This document provides an overview of the formulation and development of parenteral products. It discusses the key components including containers, closures, processing, formulation, production facilities, and evaluation methods. The production area is divided into five sections - cleanup, preparation, aseptic, quarantine, and finishing/packaging areas. Parenteral formulations contain active drugs, vehicles, and adjuvants. Finished products undergo sterility, clarity, leakage, pyrogen, and assay testing to ensure quality control.
This document provides an overview of mouth dissolving films as an innovative drug delivery system. It discusses the anatomy and physiology of the oral cavity, advantages and disadvantages of mouth dissolving films, and the role of saliva. It also covers formulation ingredients, preparation methods like solvent casting, and evaluation parameters for mouth dissolving films such as mechanical properties, disintegration time, and in vitro dissolution testing. The document aims to educate about this drug delivery system for pediatric and geriatric patients.
This document discusses the design and evaluation of bioequivalence studies. It defines bioequivalence as the absence of a significant difference in the rate and extent to which the active drug becomes available at the site of action when administered under similar conditions. The document discusses various study designs including crossover, replicate, and non-replicate designs. It also covers sampling, criteria for comparisons between test and reference products, and the roles of bioequivalence studies in drug review and approval processes.
The document discusses bioequivalence, which refers to two drug products having the same rate and extent of absorption. There are two types of bioequivalence testing: in vivo, which involves human subjects; and in vitro, which involves dissolution testing. In vivo testing is generally required for immediate-release oral drugs that are systemically absorbed, have a narrow therapeutic index, or have complicated absorption properties. In vitro dissolution testing may suffice in some cases, such as when only the drug strength differs between products or when an acceptable in vitro-in vivo correlation exists.
This document discusses quality control tests for topical preparations, including transdermal drug delivery systems (TDDS). It describes various types of topical preparations like creams, ointments, gels, pastes, and jellies. It also discusses the common ingredients in TDDS like drugs, liners, adhesives, permeation enhancers, backing layers, and polymer matrices. Finally, it outlines the key physicochemical tests performed for quality control of TDDS, including thickness, weight uniformity, drug content, content uniformity, moisture content, and moisture uptake testing.
This document discusses phytosomes, which are herbal extracts bound to phospholipids. Phytosomes have several advantages over traditional herbal extracts, including enhanced absorption and bioavailability. The document outlines the structure and properties of phytosomes, comparing them to liposomes. It also describes the preparation process, evaluation methods, and applications of various phytosome formulations. Common phytosomes include silymarin (milk thistle) for liver health, grape seed for antioxidants, green tea for antioxidants and chronic diseases, and curcumin for anti-inflammatory effects. Phytosomes allow herbal constituents to be absorbed more effectively and produce better results than conventional herbal extracts.
This document discusses various types of pharmaceutical excipients used in compounding dosage forms. It lists 16 important excipients including antioxidants, preservatives, acidifying agents, and alkalizing agents. Details are provided on the chemistry, physical properties and uses of some specific excipients including ascorbic acid, BHA, chlorobutanol, sodium bicarbonate and sodium carbonate. Excipients are added to drugs to provide suitable consistency or form and aid in compounding pharmaceutical products.
Cold cream , vanishing cream , IDEAL PROPERTIES OF VANISHING CREAMS , MAJOR INGREDIENTS USED FOR THE PRODUCTION OF VANISHING CREAMS , FORMULATION OF VANISHING CREAM , IDEAL CHARACTERISTICS OF COLD CREAM , INGREDIENTS USED FOR PREPARATION OF COLD CREAM , FORMULATION OF COLD CREAM
This document defines soft gelatin capsules and describes their anatomy, manufacturing process, quality considerations, and types. Soft gelatin capsules have a soft gelatin shell containing liquids, suspensions, or semisolids. The shell is made of gelatin, plasticizer, and water. The content can be liquids, solutions, or suspensions. The manufacturing process involves making the gel and content mixtures, encapsulating using machinery, drying, inspecting, and packaging. Quality is ensured through ingredient and in-process testing and finished product testing. Vegicaps are an alternative animal-free soft capsule with a seaweed and starch shell.
This document provides an introduction to bioequivalence studies, including definitions of key terms, the need for and importance of bioequivalence studies, criteria for establishing a bioequivalence requirement, types of bioequivalence studies, design of bioequivalence studies, evaluation of bioequivalence study results, and clinical significance. It discusses in vivo and in vitro bioequivalence study types and designs, including factors such as single dose, multiple dose, fasting, food effect, and crossover designs. Statistical evaluation methods including ANOVA, confidence intervals, and bioequivalence limits of 80-125% are also summarized.
The document discusses the manufacturing process of parenteral preparations. It describes parenterals as sterile liquids or solids for injection or implantation. The manufacturing process involves planning, material management, production, quality control testing, filling, and packaging. Production areas are divided into strict zones based on cleanliness. Environmental controls and facility design aim to prevent contamination, with areas for filling, weighing, storage, and administration. Personnel flow and utility locations are also considered for efficiency.
The document outlines the evaluation of various solid, semi-solid, and liquid dosage forms. For solid dosage forms like tablets, important tests include general appearance, weight variation, content uniformity, hardness, friability, disintegration, and dissolution. These tests are conducted to ensure quality, consistency in drug content between tablets, and that the drug will release and dissolve properly. Similar tests are described for other dosage forms like capsules, granules, powders, ointments, creams, suppositories, syrups, suspensions, emulsions, and novel delivery systems. The goal of evaluation is to quantify properties and assess interactions that impact drug stability and bioavailability.
Parenterals are formulated as solutions, suspensions, emulsions, powders, or nano systems. They contain an active ingredient, vehicle, and added substances to maintain stability and sterility. Added substances include solubilizers, antioxidants, chelating agents, antimicrobial preservatives, buffers, tonicity contributors, and protectants. Parenterals are formulated to be sterile and in stable forms like suspensions, solutions, emulsions or powders for reconstitution to facilitate easy administration while maintaining purity and therapeutic activity. They undergo quality testing for leakage, clarity, pyrogenicity and sterility.
This document discusses important considerations for dosage form design and pharmaceutical formulation. It covers topics like pharmaceutics, drug substance characteristics, excipient selection and functions, preformulation studies, stability testing, and packaging. Preformulation studies help determine appropriate dosage forms and ensure drug stability. Stability is enhanced by protecting drugs from moisture, oxygen, light and other degradation factors through packaging and formulation choices. Proper dosage form design and formulation are essential for producing effective and safe drug products.
This document discusses modified-release oral dosage forms, including extended-release and delayed-release forms. It describes various technologies used to modify drug release rates, such as coatings, matrices, and osmotic pumps. It also covers terminology, drug candidates suited for modified dosing, clinical considerations, and FDA/USP regulations regarding testing, labeling and in vitro-in vivo correlations. The goal of these dosage forms is to reduce dosing frequency while maintaining therapeutic drug levels over time.
The document discusses creams as a semisolid dosage form containing drug substances dispersed or dissolved in a suitable base. It defines oil-in-water and water-in-oil creams and provides examples of each. The key steps in cream preparation and various tests to characterize creams are described, including determining type of emulsion, viscosity, pH, globule size, stability, and spreadability. Creams offer advantages over other semisolid forms like being less greasy and more easily washed off.
Physicochemical Properties effect on Absorption of DrugsSuraj Choudhary
This document discusses factors affecting drug absorption from oral dosage forms. It covers physiological factors like gastric emptying time and pH, as well as physicochemical drug properties including solubility, dissolution rate, and polymorphism that influence drug absorption. Particle size and surface area are emphasized, with smaller particles increasing absorption for hydrophilic drugs but potentially decreasing it for hydrophobic drugs. The pH partition hypothesis and importance of drug stability are also summarized.
Pharmacokinetics / Biopharmaceutics - Bioavailability and BioequivalenceAreej Abu Hanieh
This document discusses bioavailability and bioequivalence. It defines key terms and describes how bioavailability is measured, including plasma drug concentration over time, urinary drug excretion, clinical studies, and in vitro dissolution testing. The document outlines the design of bioequivalence studies in humans and the statistical analysis used to determine if a generic drug is bioequivalent to the brand name version. It also discusses issues that can arise in bioequivalence testing.
This document discusses bioavailability and bioequivalence as it relates to drug products. It defines key terms like multisource drug products, single-source drug products, bioavailability, bioequivalence, relative bioavailability, and absolute bioavailability. It describes various methods that can be used to assess bioavailability, including pharmacokinetic methods like measuring plasma drug concentration over time and urinary excretion studies, as well as pharmacodynamic and in-vitro dissolution methods. The purpose of bioavailability studies is to ensure drug products are safe, effective, and therapeutically equivalent when generic versions enter the market after patents expire on brand name drugs.
Bioavailability and bioequivalence are important concepts for regulating generic drugs. Bioavailability refers to the rate and extent that the active drug ingredient is absorbed and available in the body. Bioequivalence means two drug products containing the same active ingredient have the same rate and extent of absorption. For approval, generic drugs must demonstrate bioequivalence to the brand name drug through pharmacokinetic studies comparing metrics like AUC and Cmax between a test and reference drug. The FDA prefers showing bioequivalence through these types of studies using a crossover design in healthy subjects under fasted conditions.
1) Bioavailability studies compare the rate and extent of absorption of a drug in its various dosage forms and are important for developing new formulations and determining generic equivalency.
2) Two main types of bioavailability are measured: absolute, which compares oral drug administration to intravenous administration, and relative, which compares different oral dosage forms.
3) Bioavailability is measured using pharmacokinetic methods like plasma concentration-time profiles and urinary excretion studies, which analyze parameters like Cmax, Tmax, and AUC. These provide information on drug absorption and bioequivalence.
This document discusses key concepts in pharmacokinetics and biopharmaceutics. It begins by defining pharmacokinetics as the study of the absorption, distribution, metabolism, and excretion of drugs in the body. The four main processes - absorption, distribution, metabolism, and excretion - are then described in more detail. Biopharmaceutics is defined as the study of how physiological factors impact drug action, including drug release and absorption. Various pharmacokinetic parameters are also introduced, including bioavailability, which measures the amount of drug that reaches systemic circulation. Methods for measuring drug concentrations in biological samples like blood, urine, and tissues are also outlined.
This document provides guidelines on bioequivalence requirements for drug products in GCC countries. It defines key terms related to bioequivalence such as pharmaceutical equivalents, generics, innovator products, and more. It explains that multi-source drug products intended to be interchangeable must demonstrate therapeutic equivalence, which can be shown through bioequivalence studies comparing the test product to a reference product. The guidelines provide details on study design for bioequivalence studies, including recommendations for non-replicate and replicate study designs depending on the drug product. It also lists acceptable methodologies for demonstrating equivalence between products.
This document discusses drug product performance and bioequivalence studies. It defines drug product performance as the release of the drug substance from the product leading to bioavailability, which relates to clinical safety and efficacy. Bioequivalence studies compare formulations and are used to assess the impact of changes to the drug substance, formulation, or manufacturing process. They can be conducted in vivo using pharmacokinetic or pharmacodynamic endpoints or in vitro using dissolution studies.
Bioavailability and bioequivalence studies are essential to ensure uniform quality, efficacy, and safety of pharmaceutical products. Bioavailability measures the rate and amount of drug that reaches systemic circulation, while bioequivalence demonstrates that generic and brand name products have comparable rates and extents of absorption. Well-designed pharmacokinetic studies are commonly used to assess bioequivalence by comparing AUC and Cmax of test and reference products. Factors like dosage form, solubility, transit time and metabolism can influence bioavailability, so studies may be necessary after manufacturing changes or for different formulations. Establishing bioequivalence allows approved generic copies to rely on the reference drug's safety and efficacy data.
Bioavailability and bioequivalence studies are essential to ensure uniform quality, efficacy, and safety of pharmaceutical products. Bioavailability measures the rate and amount of drug that reaches systemic circulation, while bioequivalence demonstrates that generic and brand name products have comparable rates and extents of absorption. Well-designed pharmacokinetic studies are commonly used to assess bioequivalence by comparing AUC and Cmax of test and reference products. Factors like dosage form, solubility, transit time and metabolism can influence bioavailability, so studies may be necessary after manufacturing changes or for different routes of administration. Guidelines regulate bioequivalence testing to allow approval of lower-cost generic drugs while maintaining therapeutic equivalence.
This document discusses bioequivalence studies and various related topics. It begins with definitions of different types of equivalence - chemical, pharmaceutical, therapeutic, and bioequivalence. It then discusses study design considerations, parameters evaluated in bioequivalence studies such as AUC and Cmax, and alternative approaches to in vivo studies including in vitro dissolution testing and biowaivers. Key points covered include the 90% confidence interval criteria applied to determine bioequivalence, crossover vs parallel study designs, and situations where in vitro methods may be acceptable for demonstrating equivalence.
Drug product performance,relative and absolute bioavailabilityChowdaryPavani
This document discusses drug product performance and bioavailability. It defines drug product performance as the release of the drug substance from the product leading to bioavailability, which is important for clinical safety and efficacy. Bioavailability studies assess how formulation changes impact pharmacokinetics. They are used in developing new and generic drug products. Bioequivalence studies specifically compare bioavailability between products to determine if they can be substituted. The document also defines relative availability as a comparison of bioavailability between a product and standard, and absolute availability as the systemic availability after non-IV dosing versus IV dosing.
This document discusses bioavailability and bioequivalence studies. It begins by introducing the importance of ensuring uniform quality, efficacy, and safety of pharmaceutical products marketed by different companies. It describes how bioavailability measures the rate and extent that a drug reaches systemic circulation, while bioequivalence ensures drugs from different sources have similar rates and extents of absorption. The document then discusses factors that can affect bioavailability like dosage form, physiology, and disease states. It also defines pharmaceutical equivalents and alternatives in establishing bioequivalence. Finally, it provides an overview of the different study designs used in pharmacokinetic studies to assess bioequivalence.
The document discusses the course contents of a biopharmaceutics and pharmacokinetics class, including definitions of key terms, factors influencing drug absorption, concepts of biological half-life and volume of distribution, drug clearance, pharmacokinetics, multiple dosage regimens, compartment models, and non-compartmental models. It provides an overview of topics that will be covered in the class relating to how the properties of drugs and dosage forms impact drug behavior in the body.
-Bioavailability and Bioequivalence-.pdfAshwin Saxena
This document discusses bioavailability and bioequivalence. It defines key terms like bioavailability, bioequivalence, and pharmaceutical equivalents. It describes important pharmacokinetic parameters used to assess bioavailability like AUC, Cmax, and Tmax. It explains the significance of bioavailability and why it is important. It also discusses various methods to determine bioavailability including plasma concentration time profiles, urinary excretion studies, and pharmacodynamic methods. The document provides an overview of requirements for bioequivalence studies by major regulatory agencies.
The document discusses several regulatory concepts and publications related to drug approval:
- The Orange Book identifies FDA-approved drug products and evaluates therapeutic equivalence of generic drugs. It aims to inform prescribing and is updated regularly.
- The Purple Book similarly lists licensed biological products, reference products, biosimilars, and exclusivity information.
- The Federal Register and Code of Federal Regulations publish and codify rules and regulations from federal agencies like the FDA. Titles and chapters address specific regulatory areas like drugs and devices.
The document provides guidelines for conducting bioavailability and bioequivalence studies in ASEAN countries. It defines key terms like bioavailability, bioequivalence, and therapeutic equivalence. The guidelines specify requirements for study design, subject selection, standardization, and data analysis to determine if test and reference products are bioequivalent and can be used interchangeably. Statistical analyses are used to assess if the products have similar rates and extents of absorption within an acceptable range.
1. Bioavailability and bioequivalence studies are essential to ensure uniform quality, efficacy, and safety of pharmaceutical products containing the same active ingredient marketed by different companies.
2. Pharmacokinetic studies measure the rate and extent of absorption of a drug from its dosage form and subsequent availability in systemic circulation. They involve measuring drug concentrations in biological fluids over time to establish equivalence between formulations.
3. Key factors in study design include subject selection criteria, sample size calculation, exclusion criteria, and genetic phenotyping to account for population diversity when assessing bioequivalence of drug products.
Bioavailability and Bioequivalence Study a concept of creating documentation in pharma industry. Students of Regulatory affairs. An explanation of the regulatory requirements while performing BA/BE studies in India. A part of PCI syllabus under subject code 104 for MPharm Sem1.
Vitamins & vitamin containing drugs manikImran Nur Manik
Vitamins are organic compounds that are essential nutrients for the human body. There are 13 essential vitamins that must be obtained through diet as the body cannot synthesize them. Vitamins play important roles in growth, development, and metabolic processes. Deficiencies can lead to specific diseases. Vitamins can be fat-soluble like A, D, E and K which are stored in the body, or water-soluble like the B vitamins and C which are not stored. Dietary sources and functions of several key vitamins are discussed.
Standardization of Acids and bases.
2. Determination of pKa and pKb values
3. Preparation of solutions of different pH & buffer capacities.
4. Determination of phase diagram of binary systems.
Determination of distribution coefficients.
6. Determination of molecular weight by Victor Meyer’s Method.
7. Determination of heats of solutions by measuring solubility as a function of temperature
(Van’t Hoff equation.)
A. Qualitative analysis of metal ions and acid radicals:
Na+, K+, Ca+2, Ag+, Mn+4, Fe+2, Fe+3, Co+2, Mg+2, Al+3, Cu+2 and acid radicals CO3,
halides, Citrate
SO4-2, NO3-, SO3-2, etc.
B. Identification of inorganic drugs in their formulation:
1. Ca+2, from supplied preparations
2. Fe+2 from supplied preparations
3. Al+3 from supplied preparations
4. Mg+2 from supplied preparations
5. K+ from supplied reparations
6. Na+ from supplied preparations
C. Conversion of different water insoluble or sparingly soluble drugs into water soluble
forms:
1. Na/ K – salicylate from salicylic acid
2. Na/ K – benzoate from benzoic acid
3. Na/ K – citrate from citric acid
Plants in complimentary and traditional systems of medicine MANIKanikImran Nur Manik
Plants in complimentary and traditional systems of medicine: Introduction-different types of
alternative systems of treatments (e.g. Ayurvedic, Unani and Homeopathic medicine). Contribution
of traditional drugs to modern medicines. Details of some common indigenous traditional drugs:
Punarnava, Vashaka, Anantamul, Arjuna, Chirata, Picrorhiga, Kalomegh, Amla, Asoka, Bahera,
Haritaki, Tulsi, Neem, Betel nut, Joan, Karela, Shajna, Carrot, Bael, Garlic, Jam and Madar.
This document provides information about various lipids (fats and oils) obtained from plants and animals. It discusses the basic chemistry of lipids, describing them as esters of fatty acids and alcohols. Specific lipids are then outlined, including their source, composition, properties, and some uses. Key lipids discussed include olive oil, coconut oil, castor oil, linseed oil, peanut oil, chaulmoogra oil, and beeswax.
Pharmacognosy is the study of medicinal plants and natural products. The term was introduced in 1815 and comes from Greek roots meaning "drug" and "knowledge." It involves the study of plants as potential drug sources from pre-historic use through various civilizations like Chinese, Babylonian, Egyptian, Indian, and Greek. Modern pharmacognosy has broad applications in medicine, agriculture, cosmetics, and other industries and offers career opportunities in academia, private industry, and government.
Crude drugs: A general view of their origin, distributions, cultivation, collection, drying and
storage, commerce and quality control.
a) Classification of drugs.
b) Preparation of drugs for commercial market
c) Evaluation of crude drugs.
d) Drug adulteration.
Carbohydrates are organic compounds made of carbon, hydrogen, and oxygen. They play a vital role in life and include monosaccharides (simple sugars), disaccharides, and polysaccharides. Common monosaccharides are glucose and fructose. Sucrose is a prevalent disaccharide composed of glucose and fructose. Starch and cellulose are examples of polysaccharides. Carbohydrates serve important functions and some like glucose are used as nutrients. Tests can identify the presence of carbohydrates and their type.
The document discusses alkaloids, which are nitrogen-containing plant compounds. It defines alkaloids and explains that they are difficult to define precisely due to overlapping properties with other amines. It then covers the distribution of various alkaloids in different plant parts, their chemical properties, pharmacological actions, classification based on ring structure, extraction methods, and chemical tests to identify alkaloids.
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive function. Exercise causes chemical changes in the brain that may help protect against mental illness and improve symptoms.
Students should calculate the time allotted per mark on their exam to help manage their time efficiently. For example, a 40 mark exam in 2.25 hours means each mark is worth 3 minutes and 22 seconds. Students should also practice solving previous years' exam questions and ensure they have the proper stationaries like pens, pencils, erasers and papers like admit cards for their exam. Proper preparation of time management and materials can help students complete their written exams successfully.
Volatile oils and related terpenoids-Methods of obtaining volatile oils,
chemistry, their medicinal and commercial uses, biosynthesis of some important
volatile oils used as drugs.
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Lecture 6 -- Memory 2015.pptlearning occurs when a stimulus (unconditioned st...AyushGadhvi1
learning occurs when a stimulus (unconditioned stimulus) eliciting a response (unconditioned response) • is paired with another stimulus (conditioned stimulus)
Co-Chairs, Val J. Lowe, MD, and Cyrus A. Raji, MD, PhD, prepared useful Practice Aids pertaining to Alzheimer’s disease for this CME/AAPA activity titled “Alzheimer’s Disease Case Conference: Gearing Up for the Expanding Role of Neuroradiology in Diagnosis and Treatment.” For the full presentation, downloadable Practice Aids, and complete CME/AAPA information, and to apply for credit, please visit us at https://bit.ly/3PvVY25. CME/AAPA credit will be available until June 28, 2025.
- Video recording of this lecture in English language: https://youtu.be/Pt1nA32sdHQ
- Video recording of this lecture in Arabic language: https://youtu.be/uFdc9F0rlP0
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
How to Control Your Asthma Tips by gokuldas hospital.Gokuldas Hospital
Respiratory issues like asthma are the most sensitive issue that is affecting millions worldwide. It hampers the daily activities leaving the body tired and breathless.
The key to a good grip on asthma is proper knowledge and management strategies. Understanding the patient-specific symptoms and carving out an effective treatment likewise is the best way to keep asthma under control.
Test bank for karp s cell and molecular biology 9th edition by gerald karp.pdfrightmanforbloodline
Test bank for karp s cell and molecular biology 9th edition by gerald karp.pdf
Test bank for karp s cell and molecular biology 9th edition by gerald karp.pdf
Test bank for karp s cell and molecular biology 9th edition by gerald karp.pdf
Nano-gold for Cancer Therapy chemistry investigatory projectSIVAVINAYAKPK
chemistry investigatory project
The development of nanogold-based cancer therapy could revolutionize oncology by providing a more targeted, less invasive treatment option. This project contributes to the growing body of research aimed at harnessing nanotechnology for medical applications, paving the way for future clinical trials and potential commercial applications.
Cancer remains one of the leading causes of death worldwide, prompting the need for innovative treatment methods. Nanotechnology offers promising new approaches, including the use of gold nanoparticles (nanogold) for targeted cancer therapy. Nanogold particles possess unique physical and chemical properties that make them suitable for drug delivery, imaging, and photothermal therapy.
These lecture slides, by Dr Sidra Arshad, offer a simplified look into the mechanisms involved in the regulation of respiration:
Learning objectives:
1. Describe the organisation of respiratory center
2. Describe the nervous control of inspiration and respiratory rhythm
3. Describe the functions of the dorsal and respiratory groups of neurons
4. Describe the influences of the Pneumotaxic and Apneustic centers
5. Explain the role of Hering-Breur inflation reflex in regulation of inspiration
6. Explain the role of central chemoreceptors in regulation of respiration
7. Explain the role of peripheral chemoreceptors in regulation of respiration
8. Explain the regulation of respiration during exercise
9. Integrate the respiratory regulatory mechanisms
10. Describe the Cheyne-Stokes breathing
Study Resources:
1. Chapter 42, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 36, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 13, Human Physiology by Lauralee Sherwood, 9th edition
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
NAVIGATING THE HORIZONS OF TIME LAPSE EMBRYO MONITORING.pdfRahul Sen
Time-lapse embryo monitoring is an advanced imaging technique used in IVF to continuously observe embryo development. It captures high-resolution images at regular intervals, allowing embryologists to select the most viable embryos for transfer based on detailed growth patterns. This technology enhances embryo selection, potentially increasing pregnancy success rates.
5-hydroxytryptamine or 5-HT or Serotonin is a neurotransmitter that serves a range of roles in the human body. It is sometimes referred to as the happy chemical since it promotes overall well-being and happiness.
It is mostly found in the brain, intestines, and blood platelets.
5-HT is utilised to transport messages between nerve cells, is known to be involved in smooth muscle contraction, and adds to overall well-being and pleasure, among other benefits. 5-HT regulates the body's sleep-wake cycles and internal clock by acting as a precursor to melatonin.
It is hypothesised to regulate hunger, emotions, motor, cognitive, and autonomic processes.
2. Bioequivalence
Table of Contents
Define AUC with its significance........................................................................................................ 1
Some Definition: ............................................................................................................................... 1
(1) Bioavailability:.......................................................................................................................... 1
(2) Bioequivalent drug product:...................................................................................................... 1
Bioequivalence ........................................................................................................................... 1
(3) Bioequivalence requirements:..................................................................................................... 2
(4) Pharmaceutical equivalents:....................................................................................................... 2
Chemical equivalents .................................................................................................................. 2
(5) Pharmaceutical alternatives: ...................................................................................................... 2
(6) Clinical..................................................................................................................................... 2
(7) Pharmaceutical substitution: ...................................................................................................... 2
(8) Therapeutic alternatives:............................................................................................................ 2
(9) Therapeutic equivalents: ............................................................................................................ 2
(10) Therapeutic substitution:.......................................................................................................... 3
(11) Brand name:............................................................................................................................ 3
(12) Chemical name: ...................................................................................................................... 3
(13) Generic name:......................................................................................................................... 3
(14) Drug product........................................................................................................................... 3
(15) Drug product selection:............................................................................................................ 3
Relative bioavailability:...................................................................................................................... 3
Absolute bioavailability:..................................................................................................................... 4
Practice Problem ............................................................................................................................ 5
Solution......................................................................................................................................... 5
Methods for Assessing Bioavailability................................................................................................. 6
tmax :The time of peak plasma concentration. ....................................................................................... 9
Significances .................................................................................................................................. 9
Cmax : The peak plasma drug concentration....................................................................................... 9
Significances .................................................................................................................................. 9
AUC: The area under the plasma level time curve. .............................................................................. 9
Significances .................................................................................................................................. 9
Procedure to obtain Duα :............................................................................................................. 11
Methods and criteria for bioavailability testing: ................................................................................. 12
Preparation of bioequivalence data: .................................................................................................. 13
Cross-over design: ........................................................................................................................ 14
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3. Bioequivalence
1. Four-way cross-over designs: ................................................................................................. 14
(ii) Three-way crossover design:................................................................................................. 15
(iii) Two-way crossover design:.................................................................................................. 16
Importance of crossover designs:................................................................................................... 16
DRUG PRODUCT SELECTION ................................................................................................... 18
Why important? ........................................................................................................................... 19
Basis for drug product selection:.................................................................................................... 19
Types of bioavailability:- .................................................................................................................. 23
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4. Bioequivalence
Prepared By: Md. Imran Nur Manik; Lecturer; Department of Pharmacy; NUB Page 1
Available at: Essential Pharma Documents
Define AUC with its significance.
AUC: AUC is a measurement of the extent of bioavailability of the drug. AUC is useful as a
measure of total amount unaltered drug that reaches the systemic circulation. AUC is dependent
on the total quantity of available drug divided by the elimination rate constant (k) and apparent
volume of distribution (VD).
D
O
VK
FD
AUCOr,
ributionlumeofdistApparantvoconstantratenEliminatio
absorbeddrugofamountTotal
AUC
Where, F= Fraction of drug absorbed
Do =Total amount of drug
After IV administration F=1, because entire dose is placed into the systemic circulation.
Therefore, the drug is considered to be completely available after IV administration. After oral
administration of the drug F may vary from 0 to 1.
Some Definition:
(1) Bioavailability:
Bioavailability may be defined as a measurement of the rate and extent to which the
therapeutically active drug reaches the systemic circulation and becomes available at the site of
action from an administered dose and dosages from.
(2) Bioequivalent drug product:
Pharmaceutical equivalents or pharmaceutical alternative products that display comparable
bioavailability when studied under similar experimental conditions are called bioequivalent
drug products.
Bioequivalence
When two related drugs show comparable bioavailability and reach the systemic circulation at
the same relative rate and extent then they are called bioequivalent and this phenomenon is
called bioequivalence.
Some drugs maybe considered as bioequivalent which are equal in the extent of absorption but
not in the rate of absorption. This is possible if -
- The difference in the rate of absorption is not clinically significant.
- It is not essential for the attainment of effective drug concentration in the body on chronic
use.
- It is reflected in the proposed labeling.
Md.
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5. Bioequivalence
Prepared By: Md. Imran Nur Manik; Lecturer; Department of Pharmacy; NUB Page 2
Available at: Essential Pharma Documents
For example, Aspirin and paracetamol are well absorbed drugs and have small differences in
the rate of absorption are very little clinical consequence.
(3) Bioequivalence requirements: It is a requirement imposed by the FDA for in vitro
and/or in vivo testing of specified drug products which must be satisfied as a condition for
marketing.
(4) Pharmaceutical equivalents: Drug products that contain the same active ingredients
(i.e. the same salt, esteron, chemical form) and are identical in strength or concentration,
dosage form, and route of administration (e.g. diazepam,5mg oral tablets) are called
pharmaceutical equivalents.
Chemical equivalents are pharmaceutical equivalents. pharmaceutical equivalent drug
products must meet the identical standards (strength, quality, purity and identity),but may
differ in such characteristics such as color, flavor, shape, scoring configuration, packaging,
excipients, preservatives, expiration time and labeling.)
(5) Pharmaceutical alternatives: Drug products that contain the same therapeutic
moiety but as different salts, esters or complexes are called pharmaceutical alternatives.
For example, tetracycline phosphate or tetracycline hydrochloride equivalent to 250mg
tetracycline base considered pharmaceutical alternatives.
(6) Clinical equivalence: Clinical equivalence occurs when the same drug; active
ingredients from two or more dosage form gives identical in vivo effects. It is measured by
pharmacological responses or by controlled symptoms or disease.
(7) Pharmaceutical substitution: It is the process of dispensing a pharmaceutical
alternative for (in the place of) the prescribed drug product.
For example, ampicillin suspension is dispensed in place of ampicillin capsules, or tetracycline
hydrochloride is dispensed in place of tetracycline phosphate. Pharmaceutical substitution
generally requires the physician's approval.
(8) Therapeutic alternatives: Drug products containing different active ingredients that
are indicated for the same therapeutic or clinical objectives are called therapeutic alternatives.
Active ingredients in therapeutic alternatives are from the same pharmacologic class and are
expected to have the same therapeutic effect when administered to patients.
For example, cimetidine can be used in the place of ranitidine because both are H2 receptor
blockers.
(9) Therapeutic equivalents: Drug products that contain the same therapeutically active
ingredient that would give the same therapeutic effect and have equal adverse effects are called
therapeutic equivalents. Therapeutic equivalents drug products may differ in certain
characteristics such as color, scoring, flavor, configuration, and packaging, preservation and
expiration date.
Md.
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6. Bioequivalence
Prepared By: Md. Imran Nur Manik; Lecturer; Department of Pharmacy; NUB Page 3
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Therapeutic equivalent drug products must satisfy the following FDA requirements. They should
be
- Safe and effective
- Pharmaceutically equivalents
- Bioequivalent
- Adequately labeled
- Manufactured in compliance with the current good manufacturing practices.
(10) Therapeutic substitution: Therapeutic substitution is the process of dispensing a
therapeutic alternative in place of prescribed drug product. For example, amoxicillin is
dispensed instead of ampicillin.
(11) Brand name: Brand name is the trade of the drug product. It is used by a manufacturer
or distributor for identification and differentiation of the specific drug product from other
competitor's products.
e.g. Napa, Nipa and APA are brand names of paracetamol and their respective companies are
Beximco, Nipa and Opsonin.
(12) Chemical name: Chemical name is the name which is used by organic chemists to
indicate the chemical structure of the drug/compound.
e.g. N-acetyl-para-aminophenol is the chemical name of paracetamol.
(13) Generic name: Generic name is the established nonproprietary or common name of
the active drug ingredients in a drug product. e.g. acetaminophen
(14) Drug product: It is the finished dosage form that contains the active ingredient in
association with additives. e.g. Paracetamol Tab, Cab. Syr.
(15) Drug product selection: The process of selecting or choosing the drug product in a
specified dosage form is called drug product selection.
Relative bioavailability:
Relative bioavailability is a measure of the fraction (or percentage) of a given drug that is
absorbed intact into the systemic circulation from an administered dosage form; relative to a
recognized (i.e. clinically proven) standard dosage form of that drug, which is either an orally
administered dosage form e.g. solution of the drug or an established suitable commercial
preparation.
The relative bioavailability of two drug products given at the same dosage level and by the
same route of administration can be determined with the following equation:
Md.
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7. Bioequivalence
Prepared By: Md. Imran Nur Manik; Lecturer; Department of Pharmacy; NUB Page 4
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StandardT
TestT
AUC
AUC
ilitybioavailabRelative
Where,(AUCT)test and (AUCT)standard are total areas under the plasma time concentration
curve following the administration of a single dose of the test and standard dosage from
respectively. This fraction may be multiplied by 100 to give percent relative availability.
When different doses of the test and standard dosage forms are administered, then a
correction for the size of dose is made as follows:-
StandardStandardT
tTesTestT
/DAUC
/DAUC
ilitybioavailabRelative
Where, D test and D standard are the sizes of the single doses of the test and standard
dosage form respectively.
Using urinary data, relative bioavailability can be calculated by the following equation:-
Standard
Test
Du
Du
ilitybioavailabRelative
Where [Du]α
test and [Du]α
Standard are the total cumulative amounts of unchanged drug
ultimately excreted in urine, following the administration of single doses of the test and standard
dosage form respectively.
If different doses of the test and standard dosage forms are administered, then a correction for
the size of dose is made as follows:-
StandardStandard
tTesTest
/DDu
/DDu
ilitybioavailabRelative
Absolute bioavailability:
The absolute bioavailability is the fraction (or percentage) of the administered dose of a given
drug from a dosage form, which is absorbed intact into the systemic circulation.
Absolute bioavailability may be measured by comparing the total amount of intact drug that
reaches the systemic circulation after administration of a known dose of the dosage form with
the total amount of intact drug that reaches systemic circulation after administration of an
equivalent dose of the drug in the form of intravenous bolus injection.
Absolute bioavailability by using plasma data can be measured as follows:-
IVT
AbsT
AUC
AUC
ilitybioavailabAbsolute
Where, (AUCT)abs = AUC after administration of a single dose of drug via a given absorption
site and (AUCT)i,v. = AUC for the drug given by via rapid intravenous injection.
Md.
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8. Bioequivalence
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If different doses of drugs are administered by both routes a correction for the sizes of the
doses is made, as in the following equation:-
IVIVT
AbsAbsT
/DAUC
/DAUC
ilitybioavailabAbsolute
Using urinary data absolute bioavailability maybe calculated as follows :-
IVIV
AbsAbs
/DDu
/DDu
ilitybioavailabAbsolute
Absolute bioavailability is sometimes expressed as a percent i.e. F=1 or 100% ( F is the fraction
of the dose that is bioavailable).
For drugs given intravascularly, such as by IV bolus injection, F = 1 because the entire drug is
completely absorbed. For all extravascular routes of administration, such as the oral route (PO),
the absolute bioavailability F may not exceed 100% (F > 1).
Q. What is the difference between relative and absolute bioavailability? [00,01 ,07]
Q. How can you calculate the dose and doses frequency from the bioavailability data?
Q. Show that AUC is the usual case of drug administration.
Practice Problem
The bioavailability of a new investigational drug was studied in 12 volunteers. Each volunteer
received either a single oral tablet containing 200 mg of the drug, 5 mL of a pure aqueous
solution containing 200 mg of the drug, or a single IV bolus injection containing 50 mg of the
drug. Plasma samples were obtained periodically up to 48 hours after the dose and assayed for
drug concentration. The average AUC values (0 to 48 hours) are given in the table below. From
these data, calculate (a) the relative bioavailability of the drug from the tablet compared to the
oral solution and (b) the absolute bioavailability of the drug from the tablet.
Drug Product Dose (mg) AUC ( μg hr/mL) Standard Deviation
Oral tablet 200 89.5 19.7
Oral solution 200 86.1 18.1
IV bolus injection 50 37.8 5.7
Solution
The relative bioavailability of the drug from the tablet is estimated using following equation:
StandardT
TestT
AUC
AUC
ilitybioavailabRelative
No adjustment for dose is necessary.
04.1
1.86
89.5
ilitybioavailabRelative
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9. Bioequivalence
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The relative bioavailability of the drug from the tablet is 1.04, or 104%, compared to the
solution.
The absolute drug bioavailability from the tablet is calculated using following equation and
adjusting for the dose.
IVIVT
AbsAbsT
/DAUC
/DAUC
ilitybioavailabAbsolute
592.0
37.8/50
89.5/200
ilitybioavailabAbsolute
Because F, the fraction of dose absorbed from the tablet, is less than 1, the drug is not
completely absorbed systemically, as a result of either poor absorption or metabolism by first-
pass effect.
Q. Name the different methods of measuring bioavailability. Which method is best and why?
Methods for Assessing Bioavailability
There are several different direct and misdirect methods are available for assessing
bioavailability of drug in humans. The selection of method depends on
- The purpose (objectives) of the study
- The ability of analyze the drug and metabolites in biological fluids
- The pharmacodynamics of drug substance.
- The route of drug administration
- And the nature of the drug products
Q. Briefly describe the common methods of assessing bioavailability.
The following methods are used to determine drug bioavailability of a drug from a drug product
(1) Clinical observations e.g. Well-controlled clinical trials
(2) Quantification of acute pharmacological effect.
(3) Measurement of plasma drug concentration using plasma level time curve.
4) Measurement of urinary drug excretion
(5) In vitro studies e.g. Dissolution
The following data are used when this is determined by acute pharmacodynamic effect
a) Maximum pharmacodynamic effect (E max)
b) Time for maximum pharmacodynamic effect
c) Area under the pharmacodynamic effect time curve
d) Onset time for pharmacodynamic effect
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10. Bioequivalence
Prepared By: Md. Imran Nur Manik; Lecturer; Department of Pharmacy; NUB Page 7
Available at: Essential Pharma Documents
When bioavailability is determined by measuring plasma drug concentration, using plasma
drug concentration time curve, the following data are used -
(a) The time for peak plasma concentration (Tmax).
(b) The peak plasma drug concentration (Cmax).
(c) The area under the plasma level time curve (AUC).
The following data are used when this is determined from urinary drug excretion
(a) The cumulative amount of drug excreted in the urine. [Du]α
(b) The rate of drug excretion in the urine (dD u/dt)
(c) The time for maximum urinary excretion (tα
)
Q. describes the method of clinical observations in determining the bioavailability. Why this method
is not used in routine bioequivalence.
(1) Clinical observation : Well-controlled clinical trials in human is carried out to
establish the safety and effectiveness of the drug product and such studies must be carried out
by manufacturers before a new drug product is finally approved for marketing.
The clinical trials approach is the least accurate least sensitive and least reproductive of the
general approaches for determining in vivo bioavailability. The FDA considers these
approaches only when analytical & pharmacological methods are not available. Although this
method would give an adequate estimation of drug in body fluids, but an adequate assay could be
developed at first.
This is the most appropriates method for determining the bioavailability of topical products,
where no in vivo bioavailability testing is possible.
e.g. The determination of bioequivalence of two topical antifungal products, made by different
manufacturers containing the same active antifungal agent. .e.g. Ketoconazole.
Drawback: Because of high costs complexity this method is not suitable for routine
bioequivalence studies.
(2) Quantification of pharmacological effect: This method assumes that a given
intensity of response is associated with a particular drug concentration at the site of action. If
adequate amount of drug is available at the site of action then pharmacological response is
produced. The observation of more intensities of response indicates the drug is more
bioavailable at the site of action. If the dose of a particular dosage form is increased the intensity
of response also increases.
Md.
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11. Bioequivalence
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Available at: Essential Pharma Documents
For example, the miotic effect after oral administration of different doses of chlorpromazine was
observed and the following curve was obtained-
Intensityofmioticresponse
Drawback: This method to assess bioavailability is approved when assay methods are not
available for detecting small quantity of drugs in the body fluids. Moreover, the monitoring of
pharmacological data is not easy and is very difficult to establish for routine use.
There are only a limited number of pharmacological effects e.g. heart rate, blood pressure,
blood sugar levels, body temperature, ECG changes that might be monitored by this method.
Direct method
(3) Measurement of plasma drug concentration: Measurement of drug
concentrations in blood, plasma, or serum after drug administration is the most direct and
objective way to determine systemic drug bioavailability. A number of good analytical
techniques such as HPLC, RIA (Radioimmunoassay), gas chromatography-mass spectroscopy
(GC-MS), have
been developed
to detect drug
and drug
metabolites in
blood urine.
[05, 09] This is
the method of
choice for
determining in
vivo
bioavailability of
drug and in
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routine bioavailability studies because it is relatively easy to study and requires a limited
number of patients; moreover it is applicable to all doses forms which are intended to deliver
the drug in to the systemic circulation.
tmax :The time of peak plasma concentration.
tmax corresponds to the time required to reach maximum (peak) drug concentration in the
plasma (blood) after drug administration.
Significances
i) At tmax, peak (maximum) drug absorption occurs and the rate of drug absorption exactly
equals the rate of drug elimination.
ii) tmax, indicates the rate at which a drug from a dosage form is absorbed into the systemic
circulation via an absorption site.
iii)The drug that reaches the systemic circulation at a faster rate will have a faster onset of
action.
Units for tmax are: hours and minutes.
Cmax : The peak plasma drug concentration.
Cmax, represents the maximum plasma drug concentration obtained after oral administration of
drug.
Significances
i) For many drugs, a relationship is found between the pharmacodynamic drug effect and the
plasma drug concentration.
ii) Cmax provides indications that the drug is sufficiently absorbed systemically to provide a
therapeutic response.
iii)In addition, Cmax provides warning of possibly toxic levels of drug.
Units for Cmax are: concentration units (e.g. mg/mL, ng/mL).
AUC: The area under the plasma level time curve.
AUC is a measurement of the extent of drug bioavailability.
Significances
i) The AUC reflects the total amount of active drug that reaches the systemic circulation.
ii) The AUC is the area under the drug plasma level time curve from t = 0 to t =α, and is equal to
the amount of unchanged drug reaching the general circulation divided by the clearance.
D
OO
kV
FD
Clearance
FD
0
0
p0
AUC
dtCAUC
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13. Bioequivalence
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Where F = fraction of dose absorbed, D0 = dose, k = elimination rate constant, and VD = volume
of Distribution.
The AUC can be determined by a numerical integration procedure, such as the trapezoidal rule
method. Units for AUC are: concentration time (e.g. μg hr/mL).
iii) AUC is independent of route of drug administration and drug elimination process but
dependent on dose of administration until the the elimination process unchanged. For example,
if a single dose of a drug is increased from 250 to 1000 mg, the AUC will also show a fourfold
increase.
iv) In some cases, the AUC is not directly proportional to the administered dose for all dosage
levels. For example, as the dosage of drug is increased, one of the pathways for drug
elimination may become saturated, then AUC does not increases proportionally with the dose ,
because a small amount of drug is being eliminated and more drug is retained.
Fig A: Plasma level time curve following administration of single doses of (A) 250 mg, (B) 500
mg, and (C) 1000 mg of drug.
Fig B: Linear relationship between AUC and dose (data from).
Fig C: Relationship between AUC and dose when metabolism is saturable.
Drug elimination includes the processes of metabolism and excretion, while drug metabolism is
an enzyme-dependent process. For drugs such as salicylate and phenytoin, continued increase
of the dose causes saturation of one of the enzyme pathways for drug metabolism and
consequent prolongation of the elimination half-life. Thus the AUC increases disproportionally
with the increase in dose, because a smaller amount of drug is being eliminated (i.e., more drug
is retained).
Disadvantages: When the AUC is not directly proportional to the dose, bioavailability of the
drug is difficult to evaluate because drug kinetics may be dose dependent.
Fig:A
Fig:B
Fig:C
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Indirect method for determining bioavailability
(4) Measurement of bioavailability by Urinary Drug Excretion Data:
Determination of bioavailability by urinary drug excretion data is an indirect method. For
estimating bioavailability the drug must have the following characteristics;
i) The drug must be excreted in significant quantities as unchanged drug in the urine.
ii) Urine samples must be collected timely. and
iii) The total amount of urinary drug excretion must be obtained.
In this case the following data are used.
Duα
: The cumulative amount of drug excreted in the urine.
Duα
is directly related to the total amount of drug absorbed. That is the higher the cumulative
value, the higher the drug absorbed.
Procedure to obtain Duα : Experimentally, urine samples are collected periodically after
administration of a drug product. Each urine specimen is analyzed for free drug using a specific
assay method. Then the cumulative amount of drug excreted in the urine is plotted against time,
fig.B.
Suppose a single dose of two tablet formulation (Tablet A and Tablet B) were administered and
when the urine sample was analyzed then fig.C was obtained. The curves in fig. C shows that
the drug in a tablet A has a much higher cumulative value then drug in tablet B. Hence, the drug
in tablet A is much more absorbed then from tablet B.
When the drug is completely eliminated pint C in the fig. A& B, the plasma concentration
approaches 0 and the maximum amount of drug excreted in urine (Duα
) is obtained.
dDuα
/dt: The rate of drug excretion in the urine
As most of the drugs are eliminated by a first-order rate process, the rate of drug excretion
(dDuα
/dt) is dependent on the first-order elimination rate constant k and the concentration of
drug in the plasma Cp.
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15. Bioequivalence
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So, when dDuα
/dt (rate of drug excreted in urine) reaches its maximum level, it indicates the
Cmax level. Because at Cmax the drug reaches its maximum level in plasma, so at this level the
rate of drug excretion would be maximum according to first-order elimination.
In the figure fig. A& B the maximum rate of drug excretion at point is at point B, whereas the
minimum rate of drug excretion is at points A and C. Thus, a graph comparing the rate of drug
excretion with respect to time should be similar in shape as the plasma level time curve for that
drug.
t∞ The total time required for the drug to be excreted.
In the above figures (fig. A& B ) the slope of the curve segment from A to B is related to
the rate of drug absorption, whereas point C is related to the total time required (after drug
administration) for the drug to be absorbed and completely excreted ( t = ∞) . The t∞ is a useful
parameter in bioequivalence studies that compare several drug products.
According to first order kinetics the drug will not completely eliminated, so the “t” is never zero
and will not touch the X axis.
03: How does the nature of food, affect the bioavailability of drug?
02,06: What do you mean by 75/75 requirement for drug product selection?
06: What is bioavailability testing? What are the criteria and waiver for testing?
Methods and criteria for bioavailability testing:
[09] Method: The general method of bioavailability testing involves:
(i) Administering a drug to a healthy human subject.
(ii) Obtaining serial blood or urine samples over a period of time.
(iii) Analyzing the samples for drug content.
(iv) Tabulating and graphing the results.
(v) Statistical tests are used to determine if any differences observed during the study.
[08] Criteria: The criteria’s of bioavailability testing are:
(i) Test should be conducted in a cross-over design to minimize the effect of individual subject
variation to drug.
(ii) At least 12 subjects should be used, although 18 to 24 subjects are used to increase the data
base for statistical analysis.
(iii) Informed, written consent should be taken from each of the individual/subject.
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(iv) Adequate examination and laboratory tests (hematology, blood chemistry and urine
analysis) are carried out to establish, the human subjects as healthy volunteers.
(v) Healthy human subjects should weigh between 55-95 kg and the individual weight of
subjects should be closed to the desirable weight for height frame and age.
(vi) The subjects should not take any drugs prior and during the study.
(vii) Food and fluid intake prior to and during the test must be kept uniform.
(viii) Usually the volunteers fast overnight and should take the drug at first in the morning with
prescribed amount of water.
(ix) A time period of 3 weeks equivalent to 10 average half-lifes, should separate the cross over
test.
(x) Test should be conducted compared with the reference standard products.
(xi) Test should be conducted in a suitable time period so that adequate data such as serum
drug concentration vs time and urine drug concentration vs time can be obtained; from which
peak serum drug level Cmax and its time, tmax and AUC can be obtained.
(xii) For the following information; different studies are used to determined bioavailability:-
(a) The drug product for topical preparation.
(b) The drug product which are administered orally but is not intended to be absorbed
(antacid).
(c) The drug products which are administered by inhalation as a gas or vapor (e.g. inhaler).
[98] What is the information’s to be included in bioequivalence data? How you will present a
bioequivalence data?
Preparation of bioequivalence data: Bioequivalence study data should be
presented so that the important factors like -
- Peak serum concentration (Cmax),
- The time for peak plasma concentration (tmax),
- AUC : Area Under Plasma Drug Concentration curve can readily and adequately be
evaluated.
This presentation usually involves a format that includes- (i) tabulated data and (ii) drug
concentrations versus time figure.
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The following factors are included to the formula representing bioequivalence data -
1. Name and manufacturer of drug
2. Dosage form of drug.
3. Number of volunteers and number of each sex.
4. Types of analytical producers used in the study.
5. Type of study.
6. Sampling intervals.
7. Drug concentration at each sampling intervals.
8. Average of individual peak serum drug concentration.
9. Average of the times for peak serum drug concentration.
10. AUC for the various time intervals. (Ave. AUC)
11. Statistical method used to evaluate the data.
12. The result of the statistical evaluation.
[97:] What do you mean by Crossover Designs? What are the advantages of Crossover Designs in
bioequivalence testing?
Cross-over design: A simple study design can lead to false information due to 3 reasons as
follows:-
(i) Different subject population,
(ii) Different study conditions,
(iii) Different assay methodology.
The errors arising from the above three causes may overcome by studying cross-over design.
In the cross-over design, all individual subjects receive each formulation once. A suitable cross-
over design should be utilized in bioavailability testing, so that subjects daily variation are
equally distributed among all dosage forms or drug products being tested.
Types of cross-over designs: There are three types of cross-over designs;-
1. Four-way cross-over design.
2. Three-way cross-over design
3. Two-way cross-over design.
1. Four-way cross-over designs: In a 4-way cross-over design, four different drug foundation
(A, B, C, D), are used in 12 volunteers , divided in 4 groups for the bioavailability study. This
type of design plans the clinical trail so that each subject receives each drug product only once.
An adequate time is allowed between the medications (two successive administration of the
drug) for the elimination of the drug from the body.
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Thus the drug product B may be followed by drug product A, D or C. A four way cross over
design may be described as follows:-
Subjects
in groups
Drug Product
Study Period 1 Study Period 2 Study Period 3 Study Period 4
1,2,3 A B C D
4,5,6 B C D A
7,8,9 C D A B
10,11,12 D A B C
Table : 4-way cross-over design for a bioequivalence study of 4 different drug products in 12
human volunteers dividing them into 4 groups. All subject (each group) received each drug
product only once without repetition.
After each subject receives a drug product, the blood samples are collected at an appropriate
time intervals so that a blood drug level-time curve is obtained. The time intervals should be
sufficiently spaced so that the peak blood concentration, the AUC, and the absorption and
elimination phases of the curve may be well described. In some cases, the measurement of drug
in urine samples may be necessary.
(ii) Three-way crossover design:
In a three-way cross-over design, three different drug foundation (say A,B,C) are used in 6
volunteers for a bioequivalence study. In this design, each subject receives each drug product
only once, with adequate time between medications for the elimination of the drug from the
body. Thus, drug product a may be followed by B or C.
A three way cross-over design maybe expressed as the following tabulating form:-
Drug Product
Subject Study Period 1 Study Period 2 Study Period 3
1 A B C
2 B C A
3 C A B
4 A C B
5 C B A
6 B A C
Table : A three-way cross-over design for a bioequivalence study of 3 drug products in 6 human
volunteers.
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(iii) Two-way crossover design:
In a two-way crossover design, two different drug products 9A,B) are used in two groups of
volunteers or two volunteers.
Subjects/Groups
Drug Product
Study Period 1 Study Period 2
1 (6 Subjects) A B
2 (6 Subjects) B A
Table: A two-way cross-over design for a bioequivalence study of 2 different drug products.
Importance of crossover designs:
(i) These designs reduce subject to subject variation in bioequivalence study.
(ii) Variation due to sequence, period, and treatment (formulation) is reduced; because all
patients do not receive the same drug product on the same day and in the same order
(iii) Possible carry-over effects from any particular drug product are minimized by changing
the sequence or order in which the drug products given to the subject.
Advantage:
The limitation of simple bioavailability study can be overcome by using this process.
[02] Wash-out period:
The time during which most of the drugs are eliminated from the body is called the washout
periods. Generally about it is about 10 elimination half-lives of a drug product.
[02] Question: Theophylline has a half-life of 3 hours. Calculate the wash out period of
theophylline.
Answer: We know, wash out period is about 10 elimination half life of a drug product.
Thus the wash out period of theophylline= 10 t1/2=10×3=30 hours.
[01,04,07,09] Purposes of bioavailability studies :
(i) Bioavailability studies are performed for both approved active drug ingredients and
therapeutic moieties which are yet to be approved for marketing by FDA. To be approved by
the FDA, the drug products must be safe and effective and must meet all applicable standards of
strength, quality and purity. To ensure these standards the FDA requires bioavailability or
pharmacokinetic studies and where necessary bioequivalence studies for all drug products.
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(ii) For un-marketed drug products, in-vivo and in-vitro bioequivalence studies must be
performed on the drug formulation proposed for marketing as a generic drug product.
Furthermore, the essential pharmacokinetic parameters of the active drug ingredient or
therapeutic moiety must be characterized, Essential pharmacokinetic parameters including the
Rate and extent of systemic drug absorption,
Rates of excretion & metabolism and
Elimination half-life should be determined after administration of single as well as multiple
doses. The bioavailability study data are important to establish recommended dosage regimens
and to support drug labeling.
(iii) In-vivo bioavailability studies are also performed for new formulations or therapeutic
moieties that are fully approved for marketing. The purpose of these studies is to determine the
bioavailability and to characterize the pharmacokinetics of the new formulations, new dosage
from, new salt or ester with respect to a reference standard formulation.
(iv) Clinical bioavailability studies are useful in determining the safety and efficacy of the drug
products.
(v) Bioavailability studies are used to define the effect of changes in the dosage form and
physicochemical properties of drug products on the pharmacokinetic of the drug.
(vi) Bioequivalence studies are used to compare the bioavailability of the same drug (same salt
or ester) from various drug products.
(vii) Bioavailability and Bioequivalence can also be considered as performance measures of the
drug products in-vivo.
Question: What do you mean by bioequivalence requirement? What are the criteria for establishing a
bioequivalence requirement?
Answer: [2000, 99] Bioequivalence requirement: A requirement imposed by the FDA for in-
vitro and/ or in-vivo testing of specified drug product. This requirement must be satisfied as a
condition for marketing.
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[2000, 97] Criteria for establishing a bioequivalence requirement:
Bioequivalence requirements may be imposed by FDA on the basis of the following:
1. Evidence from well controlled clinical trials, or controlled observations in patients and
bioequivalence studies:
Various drug products do not give comparable therapeutic effects are not bioequivalent
drug products.
Narrow therapeutic ratio and minimum effective concentration in the blood.
Serious adverse effects.
2. Physicochemical:
Low solubility in water.
Dissolution rate slow.
Particle size and surface area of the effective drug ingredient.
Structural forms dissolve slowly.
High ratio of excipients.
Hydrophilic or hydrophobic excipients and lubricants
3. Pharmacokinetic:
GI or localized site
Degree of absorption poor.
Period: Period refers to the time period in e a study is performed. A two period study is a study
that is performed on 2 different ways.
Sequence: A sequence refers to the no of different orders in the treatment groups in a study.
For groups a two sequence, two period studies would be designed as follows:-
Period 1 Period 2
Sequence 1 T R
Sequence 2 R T
Where, R = Reference and T= Treatment
DRUG PRODUCT SELECTION
Nowadays the pharmacists are playing an important role in drug product selection. Prescription
in which the product selection is permitted, (saying that, “product selection is permitted”)
pharmacist can select an equivalent drug product as he dispenses.
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The hospitals or countries where there is a formulary system, the pharmacists are allowed to
select an equivalent drug product from those listed in the formulary.
Proper of a multi-source drug products is a major role and responsibility of the pharmacist. All
heath practitioners should be aware that biopharmaceutical principles can provide a sound
basis for rational drug product selection.
Why important?
Drug product selection is very important because-
1. The drug products from different manufacturers which contain the same amount of active
ingredient may perform differently in patients.
2. Differences in formulation can cause significant differences in the bioavailability of the
drug. Most of the problems are associated with more compact dosage from e.g. capsules
and tablets.
3. Manufacturing process and materials used in the formulation of a drug product may very
considerably from one drug manufacturer to other.
Therefore, it is not surprising that the various drug products of the same drug entity may exhibit
different bioavailability characteristics.
Basis for drug product selection:
a. Types of cross-over study
b. Number of sample used.
c. Number of subject used.
d. Factors such as age range, weight range and sex of the subject.
e. Types of analytical procedure used.
f. The strength and type of dosage form used
B. Bioavailability data:
Blood level drug concentration and urinary drug excretion data can be used to compare the
bioavailability of a specific drug form and under various conditions. Blood level curves and
urinary drug excretion profile can be used to evaluate the bioavailability of specific drug from
different drug products (various dosage forms).The data which provides the bioequivalence of
drug products will be selected. Because bioequivalent drug products maybe used as
alternatives.
Data should be evaluated carefully to decide whether a drug product whether will be accepted
or not.
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Fig. Blood level curve for meprobomate drug products.
The data in the figure indicate that the manufacturer’s drug product is equivalent to the standard
reference product against which it has been tested. The blood level of the two products is
essentially super impossible. An adequate number of subjects are used in this study. When the
drug concentration time curves for two drug products are superimposable then, there is no
problem to deduce that two drug products are equivalent. Exact super-impossibility is a rare
occurrence. If blood level curves for the drug products that two products of the same active
ingredient are significantly different, then it arises the question of “how much difference is
allowed before one of the products can be judged as bioequivalent to the reference standard
product?”
The FDA has currently proposed a 75/75 requirement for the bioequivalence studies of certain
drug products. It implies that the relative bioavailability of test product when compare to the
bioavailability of a reference products must be greater than or equal to 75% for 75% of the
subjects. When at least 75% of the subjects are administered the drug, the test drug has a
bioavailability of greater than 75% relative of the AUC and/or peak height of a reference
standard.
98, 02, 06: What do you mean by 75/75 requirements?
For some drugs with a wide margin of safety e.g. penicillin, a 25% difference in the
bioavailability might not significantly affect the clinical outcome after 1-2 weeks of therapy. On
the other hand, for drugs with a narrower margin of therapeutic effectiveness and safety, e.g.
digoxin a 25% decrease in bioavailability could cause significant adverse therapeutic effects.
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24. Bioequivalence
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The act of drug product selection is a legal responsibility. Professional responsibility is
achieved if the practitioner selects drug products on the basis of proper evaluation of
bioequivalence data. However, care must be taken to ensure that the product has been
approved by the FDA. To properly select a drug through evaluation of bioavailability, the data is
a must.
C. Other manufacturing consideration:
For many products, good bioavailability data maybe made available by many
pharmaceutical manufacturers. Therefore, other manufacturing consideration should be taken
into account when selecting a manufacturer of drug products. Some important criteria for
manufacturing products are given bellows-
(1) Upon request of the pharmacist, the supplier should furnish analytical control, sterility
testing and bioavailability data, description of testing procedures for new materials and finished
products or any other information which may be indicative of the quality of a given finished
drug product. This information should be supplied at no charge.
(2) The company should permit visits (during normal business hours) by the pharmacist to
inspect its manufacturing and control procedures.
(3) All drug products shipped to the hospital should conform to the requirements of the most
recent USP-NF criteria.
(4) The name and address of the manufacturer of the final dosage from should be present on
the product labeling.
(5) Expiration dates should be clearly indicated on the package.
(After weighing all the evidence and selecting drug product, be sure to follow through on the
pharmacist’s professional responsibility)
Thus, it is clear that health care practitioner must rely on their own judgment about the
bioavailability of drug products they dispense.
02, Methods of determining bioavailability by clinical observation:
This method is used to establish the efficacy and safety of drugs and drug products and many
such studies must be carried out by manufacturers before new product is finally approved for
marketing. These studies involve a large number of patients and are very expensive. The
subjects are diseased and the drug products are given to them and then asked about clinical
response just before dosing, at 30 minutes and one hour after dosing and at hourly intervals,
therefore a total 6 hours after dosing.
e.g. Clinical trial of analgesic zomepirac (Etodolac 400 mg) are shown in the following figure.
This study used 148 points, randomly divided into five groups and each group was given one of
the following drugs :- zomepirac 50 mg (Etodolac 400 mg); zomepirac 100 mg (Etodolac 200
mg) 100mg. APC with codein 60mg and placebo.
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25. Bioequivalence
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Figure I. Etodolac versus codeine/acetaminophen in the relief of pain from oral surgery (Mehlisch).
*Significantly (p ~<0.05) superior to placebo. +Significantly (p ~<0.05) superior to
codeine/acetaminophen. (Reproduced courtesy of the author and the editor of Rheumatology
International [21])
The patients were questioned about their pain just before dosing, at 30 minutes and 1 hour after
administration and at hourly intervals, therefore total of the 6 hours after dosing. At each
observation patients were asked to rate their pain intensity from none to severe on a four-point
scale.
98 , 02, In which cases bioequivalence test requirements are not relevant?
The followings are the cases where bioequivalence test requirements are not relevant;
(i) Certain drug products –e.g. topically applied ointments, creams, and lotions used for local
effects.
(ii) Drug products such as antacids and laxatives containing ingredient not intended for
absorption.
(iii) Intravenous solution that has the same drug concentration and solvent system, as the FDA
approved product.
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(iv) Liquid drug products that contain the active ingredients in a solubilized form (oral solution,
elixirs, syrups etc) in the same concentration as the drug product that has been the approved by
the FDA via NDA ( New Drug Administration )
Types of bioavailability:-
(i) Absolute bioavailability: - When the systemic availability of a drug administered orally
is determined in comparison to its intravenous administration, is called as absolute availability.
The absolute bioavailability of a drug in a drug product may be measured by comparing the
respective AUC, after oral or iv administration. This measurement may be performed as long as
VD & K are dependent of the route of administration.
A B A using plasma data can be determined as follows
Doral[AUC]iv.
Div[AUC]oral.
Div[AUC]iv./
/Doral[AUC]oral.
ABA
AUC = Area under the Curve
D = Dose of administered drug
ABA using urinary drug excretion data determined by the following equation:-
Doraliv.[DU]
Divoral.[DU]
Diviv./[DU]
loral./Dora[Du]
ABA
The absolute bioavailability is also equal to F, the fraction of the dose that is bioavailable.
[98,99,02]Importance of bioavailability
The importance of bioavailability are given below:
1. Bioavailability is used to ensure the strength, quality, identity and purity of a drug product.
2. It evaluates the absorption, distribution, metabolism and elimination characteristics of a drug.
3. It helps to minimize the toxic effect of a potent drug .
4. It helps to select the suitable route of drug administration.
5. Dose and frequency of dose can be determined .If the bioavailability of a drug is more then
the dose is less.
6. It helps to confirm the bioequivalence of drug product.
[01]Differentiate between bioavailability and bioavailable drug.
Bioavailability: The relative amount of an administered dose of a drug that reaches the
systemic circulation intact and the rate at which it occurs is called bioavailability of that drug.
Thus bioavailability is concerned with the amount and rate at which the intact form of a
particular drug appears in the systemic circulation following its administration.
Bioavailable dose: The fraction of an administered dose that reaches the systemic circulation
intact is called bioavailable dose.
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