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DRUG PRODUCT PERFORMANCE, IN VIVO.pptx

The document discusses drug product performance, focusing on bioavailability and bioequivalence as key factors in assessing how drugs are absorbed and utilized in the body. It explains various study designs, including fasting, food intervention, and multiple-dose studies, aimed at evaluating the bioavailability of drug formulations relative to standards. Furthermore, it emphasizes the importance of regulatory approval by the FDA to ensure drug safety and efficacy before marketing.

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1 Presented by SHAHEENA BEGUM M. Pharm- Pharmaceutics (2nd sem) DRUG PRODUCT PERFORMANCE, IN VIVO
2 FLOW OF PRESENTATION Bioavailability and Bioequivalence Drug Product Performance (In vivo) Methods for assessing bioavailability Bioequivalence studies Design and evaluation of bioequivalence studies Study designs
3 BIOAVAILABILITY Bioavailability means the rate and extent to which an active ingredient is absorbed from a drug product and becomes available at the site of action. BIOEQUIVALENCE Bioequivalence is the biochemical similarity of two (or more) drugs that share the same active ingredient(s) and desired outcome(s) for patients.
4 DRUG PRODUCT PERFORMANCE (IN VIVO)  The release of the drug substance from the drug product leading to bioavailability of the drug substance. The assessment of drug product performance is imp. Since bioavailability is related both to the pharmacodynamic responses and the adverse events. The performance tests relate the quality of a drug product to clinical safety and efficacy.  Bioavailabilty studies are drug product performance studies used to define the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug , and the manufacture process of the drug product.
BIOEUIVALENCE STUDIES IN NEW DRUG DEVELOPMENT (NDA) 5 • Used to compare : • Early and late clinical trial formulations • Formulations used in clinical trials and stability studies, if different • Clinical trial formulations and to be marketed drug products , if different
6 BIOEQUIVALENCE STUDIES IN GENERIC DRUG DEVELOPMENT (ANDA)  A generic drug product is a multisource drug product that has been approved by the FDA as a therapeutic equivalent to the reference listed drug product and has proven equivalent drug product performance.  The generic drug manufacturer must demonstrate that the generic drug product is pharmaceutically equivalent, bioequivalent, and therapeutically equivalent to the comparator brand-name drug product.
PURPOSE OF BIOAVAILABILITY STUDIES  Bioavailability studies are performed for both approved active drug ingredients and therapeutic moieties not yet approved for marketing by the FDA .  New formulations of active drug ingredients must be approved by the FDA before marketing .  FDA ensures that the drug product is safe and effective for its labeled indications for use .  The drug product must meet all applicable standards of identity , strength , quality , and purity .
 Bioavailability may be considered as one aspects of drug product quality that links In vivo performance of the drug product used in clinical trials to studies demonstrating evidence of safety and efficacy.  For unmarketed drugs that do not have full NDA approval by the FDA In vitro , and In vivo bioequivalence studies must be performed on the drug formulation proposed for marketing as a generic drug product  Furthermore , the essential pharmacokinetics of the active drug ingredient or therapeutic moiety must be characterized  Essential pharmacokinetic parameters , including the rate and extent of systemic absorption , elimination half life , and rates of excretion and metabolism , should be established after single and multiple dose administration .
 In vivo bioavailability studies are also performed for new formulation of active drug ingredients that have full NDA approval and are approved for marketing .  The purpose of these studies is to determine the bioavailability and to characterize the pharmacokinetics of new formulation, new dosage form , new salt or ester relative to a reference formulation .  Clinical studies are use full in determining the safety and efficacy of drug products .  Bioavailability studies are used to define the effect of changes in the physicochemical properties of the drug substance and effect of the drug product on the pharmacokinetics of the drug .  Bioequivalence studies are used to compare the bioavailability of the same drug from various drug products .
10 ABSOLUTE BIOAVAILABILITY  When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration , it is called as absolute bioavailability.  It is denoted by symbol F. Its determination is used to characterize a drugs absorption properties from the e.v. site. Fab = [AUC]oral Div [AUC]iv Doral
11  When the systemic availability of a drug after oral administration is compared with that of an oral standard of the same drug , It is referred to as relative or comparative bioavailability .  It is denoted by symbol Fr . It is used to characterize absorption of a drug from its formulation. RELATIVE BIOAVAILABILITY Fr = [AUC] test Dstd [AUC]std Dtest
12 METHODS FOR ASSESSING BIOAVAILABILITY  In vivo measurement of active moiety or moieties in biological fluids  Plasma drug concentration  tmax  Cmax  AUC  Urinary Drug excretion  In vivo pharmacodynamic comparison  Clinical endpoint study  In vitro studies
13 PLASMA DRUG CONCENTRATION  Measurement of drug concentration in blood , plasma , or serum after drug administration is most direct and objective way to determine systemic bioavailability.  tmax  C max  AUC
14 tmax . (The time of peak plasma concentration) tmax , corresponds to the time required to reach maximum drug concentration after drug administration . At tmax peak drug absorption occurs and the rate of drug absorption exactly equals the rate of drug elimination (fig. 15-1). Drug absorption still continues after tmax is reached, but at a slower rate . Cmax The peak plasma concentration , it represents the maximum plasma drug concentration obtained after oral administration of drug for many drugs , a relationship is found between the pharmacodynamics drug effect and the plasma drug concentration . c max provides warning of possibly toxic levels of drug the unit of cmax are concentration units eg mg/ml, ng/ml . AUC . The area under the plasma level time curve : that gives a measure of the extent of absorption or the amount of drug that reaches the systemic circulation .
15  This method of assessing bioavailability is based on the principle that the urinary excretion of unchanged drug is directly proportional to the plasma concentration of drug.  Determination of bioavailability using urinary excretion data should be conducted only if at least 20 % of administered dose is excreted unchanged in urine. URINARY EXCRETION STUDIES
16 BIOEQUIVALENCE STUDIES  Differences in the predicted clinical response or an adverse event may be due to differences in the pharmacokinetic or pharmacodynamic behaviour of the drug.  Bioequivalent drug products that have the same systemic drug bioavailability will have the same predictable drug response. However, variable clinical responses among individuals that are unrelated to bioavailability may be due to differences in the pharmacodynamics of the drug.
17 DESIGN AN EVALUATION OF BIOEQUIVALENCE STUDIES  Bioequivalence studies are performed to compare the Bioavailability of the generic drug product to the brand name product.  Statistical techniques should be of sufficient sensitivity to detect differences in rate and extent of absorption that are not attributable to subject variability.  Once bioequivalence is established, it is likely that both the generic and brand name dosage forms will produce the same therapeutic effect.
18 STUDY DESIGN  For many drug products, the FDA, Division of Bioequivalence, Office of Generic Drugs, provides guidance for the performance of in-vitro dissolution and in-vivo bioequivalence studies. Similar guidelines appear in the United States Pharmacopoeia NF.  Currently, three different studies may be required for solid oral dosage forms, including 1. Fasting study 2. Food intervention study 3. Multiple-dose study
Bioequivalence studies are usually evaluated by a single-dose, two-period, two- treatment, two-sequence, open-label, randomized crossover design comparing equal doses of the test and reference products in fasted, adult, healthy subjects .  This study is required for all immediate-release and modified-release oral dosage forms .  Both male and female subjects may be used in the study. Blood sampling is performed just before (zero time) the dose and at appropriate intervals after the dose to obtain an adequate description of the plasma drug concentration vs time profile  The subjects should be in the fasting state (overnight fast of at least 10 hours) before drug administration and should continue to fast for up to 4 hours after dosing  No other medication is normally given to the subject for at least 1 week prior to the study. FASTING STUDY :
FOOD INTERVENTION STUDY :  Co-administration of food with an oral drug product may affect the bioavailability of the drug.  Food intervention or food effect studies are generally conducted using meal conditions that are expected to provide the greatest effects on GI physiology so that systemic drug availability is maximally affected.  The test meal is a high-fat (approximately 50% of total caloric content of the meal) and high-calorie (approximately 800-1000 calories) meal.  This test meal derives approximately 150, 250, and 500 & 600 calories from protein, carbohydrate, and fat, respectively . For bioequivalence studies, drug bioavailability from both the test and reference products should be affected similarly by food.
 The study design uses a single-dose, randomized, two-treatment, two-period, crossover study comparing equal doses of the test and reference products.  Following an overnight fast of at least 10 hours, subjects are given the recommended meal 30 minutes before dosing. The meal is consumed over 30 minutes with administration of the drug product immediately after the meal .  The drug product is given with 240 mL (8 fluid ounces) of water. No food is allowed for at least 4 hours post dose .  This study is required for all modified-release dosage forms and may be required for immediate-release dosage forms if the bioavailability of the active drug ingredient is known to be affected by food (eg, ibuprofen, naproxen).
MULTIPLE-DOSE (Steady-State) STUDY  In a few cases, a multiple-dose, steady-state, randomized, two-treatment, two-way crossover study comparing equal doses of the test and reference products may be performed in adult, healthy subjects.  For these studies, three consecutive trough concentrations (C min) on three consecutive days should be determined to ascertain that the subjects are at steady state .  The last morning dose is given to the subject after an overnight fast, with continual fasting for at least 2 hours following dose administration. Blood sampling is performed similarly to the single-dose study.
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