This document provides an overview of basic concepts in biopharmaceutics including pharmacokinetic models and parameters. It discusses pharmacokinetic concepts like dosage regimen, pharmacokinetics, plasma drug concentration profiles, and pharmacokinetic parameters including Cmax, tmax, AUC, etc. It also covers pharmacokinetic models including compartment models, physiological models, and non-compartmental analysis. Specific compartment models like one-compartment open model for IV bolus and infusion administrations as well as extravascular administration are explained. Methods for estimating pharmacokinetic parameters from these models are also summarized.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
CHRONOPHARMACOKINETICS AND TIME DEPENDENT PHARMACOKINETICSN Anusha
Chronopharmacokinetic studies have been demonstrating that time of administration is a possible factor of variation in the kinetics of the drug.
It entails the study of temporal changes in drug absorption, distribution, metabolism and elimination.
It investigates the variation in drug plasma levels as a function of time of day and the mechanisms responsible for time dependant variations.
The term circadian coined by Franz Halberg, comes from Latin.
“Circa” means around &“diem” means day.
Factors affecting sustained release drug delivery system.Kavya S
contented and precise , Drug delivery system , sustained release preparation.factors like absorption, distribution ,metabolism , therapeutic window , absorption window.
The presentation concisely describes the different pharmacokinetic parameters and basics of compartment modelling. It will help undergraduate students to understand the basic concepts of Biopharmaceutics.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
CHRONOPHARMACOKINETICS AND TIME DEPENDENT PHARMACOKINETICSN Anusha
Chronopharmacokinetic studies have been demonstrating that time of administration is a possible factor of variation in the kinetics of the drug.
It entails the study of temporal changes in drug absorption, distribution, metabolism and elimination.
It investigates the variation in drug plasma levels as a function of time of day and the mechanisms responsible for time dependant variations.
The term circadian coined by Franz Halberg, comes from Latin.
“Circa” means around &“diem” means day.
Factors affecting sustained release drug delivery system.Kavya S
contented and precise , Drug delivery system , sustained release preparation.factors like absorption, distribution ,metabolism , therapeutic window , absorption window.
The presentation concisely describes the different pharmacokinetic parameters and basics of compartment modelling. It will help undergraduate students to understand the basic concepts of Biopharmaceutics.
A presentation given by a group of students of Faculty of Pharmacy, University of Dhaka, Bangladesh.
This presentation discussed with different physiolgical factors of drug absorption, structure of membrane the drug crosses, different transport mechanism etc
Physical Properties of Pre-formulation.pptxRAHUL PAL
Preformulation studies provide a path for formulation development and drug product development in respect of drug form, adjuvants, composition, physical structure, and chemistry of drug molecules, facilitating pharmacokinetic and biopharmaceutical properties evaluation, adjustments, and their implementation.
Preformulation studies focus on the concepts of physicochemical properties which are vital for any new drug molecule and/or proteins/peptides. These properties not only affect their therapeutic efficacy but also the development process of their specific dosage form.
introduction
mechanisms of protein drug binding
binding of drugs
binding of drugs to blood components
determination of protein drug binding
factors affecting
significance
Rate limiting steps in drug absorption [autosaved]Nagaraju Ravouru
Rate limiting steps in drug absorption 1.Disintegration time
2.Dissolution and solubility
3.Physical and chemical nature of active drug substance
4.Nature of excipients
5.Method of granulation
6.Dissolution test conditions
7.Gastric emptying
Methods For Assesment Of Bioavailability Anindya Jana
Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
Phase solubility analysis and pH solubility profileMohit Angolkar
A Brief presentation on the topic- phase solubility analysis and pH solubility profile, which covers the following aspects:
- Solubility introduction
- importance of solubility
- factors influencing solubility
- Phase solubility analysis introduction
- method of analysis
- purification technique
- introduction to pH solubility profile.
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
A presentation given by a group of students of Faculty of Pharmacy, University of Dhaka, Bangladesh.
This presentation discussed with different physiolgical factors of drug absorption, structure of membrane the drug crosses, different transport mechanism etc
Physical Properties of Pre-formulation.pptxRAHUL PAL
Preformulation studies provide a path for formulation development and drug product development in respect of drug form, adjuvants, composition, physical structure, and chemistry of drug molecules, facilitating pharmacokinetic and biopharmaceutical properties evaluation, adjustments, and their implementation.
Preformulation studies focus on the concepts of physicochemical properties which are vital for any new drug molecule and/or proteins/peptides. These properties not only affect their therapeutic efficacy but also the development process of their specific dosage form.
introduction
mechanisms of protein drug binding
binding of drugs
binding of drugs to blood components
determination of protein drug binding
factors affecting
significance
Rate limiting steps in drug absorption [autosaved]Nagaraju Ravouru
Rate limiting steps in drug absorption 1.Disintegration time
2.Dissolution and solubility
3.Physical and chemical nature of active drug substance
4.Nature of excipients
5.Method of granulation
6.Dissolution test conditions
7.Gastric emptying
Methods For Assesment Of Bioavailability Anindya Jana
Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
Phase solubility analysis and pH solubility profileMohit Angolkar
A Brief presentation on the topic- phase solubility analysis and pH solubility profile, which covers the following aspects:
- Solubility introduction
- importance of solubility
- factors influencing solubility
- Phase solubility analysis introduction
- method of analysis
- purification technique
- introduction to pH solubility profile.
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
This presentation will give the students a basic knowledge about the pharmacokinetics of durgs. It will help them clear the basics before digging deep into the topic.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
1. BASIC CONCEPTS OF BIOPHARMACEUTICS
Department of Pharmaceutics
Pharmacokinetic Models & Estimation of
Pharmacokinetic Parameters
2. Dosage Regimen:
The frequency of administration of a drug in a particular dose is called as
dosage regimen.
Pharmacokinetics:
Pharmacokinetics is defined as the kinetics of drug absorption, distribution, metabolism
and excretion (KADME) and their relationship with the pharmacological, therapeutic or
toxicological response in man and animals. There are two aspects of pharmacokinetic
studies –
Theoretical aspect – which involves development of pharmacokinetic models to predict
drug disposition after its administration. Statistical methods are commonly applied to
interpret data and assess various parameters.
Experimental aspect – which involves development of biological sampling techniques,
analytical methods for measurement of drug (and metabolites) concentration in
biological samples and data collection and evaluation.
3. Plasma Drug Concentration-Time Profile
A direct relationship exists between the concentration of drug at the biophase (site of
action) and the concentration of drug in plasma. Two categories of parameters can be
evaluated from a plasma concentration time profile –
Pharmacokinetic parameters, and
Pharmacodynamic parameters.
4. Pharmacokinetic Parameters
1. Peak Plasma Concentration (Cmax)
The peak plasma level depends upon –
The administered dose
Rate of absorption, and
Rate of elimination.
2. Time of Peak Concentration (tmax)
3. Area Under the Curve (AUC)
Pharmacodynamic Parameters
1. Minimum Effective Concentration (MEC)
2. Maximum Safe Concentration (MSC)
3. Onset of Action
4. Onset Time
5. Duration of Action
6. Intensity of Action
7. Therapeutic Range
8. Therapeutic Index
5. Rate, Rate Constants and Orders of Reactions
Rate: The velocity with which a reaction or a process occurs is called as its rate.
Order of reaction: The manner in which the concentration of drug (or reactants) influences
the rate of reaction or process is called as the order of reaction or order of process.
Consider the following chemical reaction:
Drug A Drug B
The rate of forward reaction is expressed as –
-dA/dt
Negative sign indicates that the concentration of drug A decreases with time t. As the
reaction proceeds, the concentration of drug B increases and the rate of reaction can also
be expressed as: dB/dt
dC/dt = -KCn
K = rate constant
n = order of reaction
6. Zero-Order Kinetics (Constant Rate Processes)
If n = 0, equation becomes:
dC/dt = -Ko Co
where Ko = zero-order rate constant (in mg/min)
Zero-order process can be defined as the one whose rate is independent of the
concentration of drug undergoing reaction i.e. the rate of reaction cannot be increased
further by increasing the concentration of reactants.
Finally C = Co – Ko t
7. Zero-Order Half-Life
Half-life (t½) or half-time is defined as the time period required for the concentration of
drug to decrease by one-half.
t1/2 = Co / 2 Ko
Examples of zero-order processes are –
1. Metabolism/protein-drug binding/enzyme or carrier-mediated
transport under saturated conditions. The rate of metabolism, binding or transport of
drug remains constant as long as its concentration is in excess of saturating
concentration.
2. Administration of a drug as a constant rate i.v. infusion.
3. Controlled drug delivery such as that from i.m. implants or osmotic
pumps.
8. First-Order Kinetics (Linear Kinetics)
If n = 1, equation becomes:
dC/dt = - K C
where K = first-order rate constant (in time–1 or per hour)
first-order process is the one whose rate is directly proportional to the concentration of
drug undergoing reaction i.e. greater the concentration, faster the reaction. It is because
of such proportionality between rate of reaction and the concentration of drug that a
first-order process is said to follow linear kinetics.
9. ln C = ln Co - K t
C = C o – e –Kt
log C = log Co – Kt/2.303
The first-order process is also called as monoexponential rate process. Thus, a first-order
process is characterized by logarithmic or exponential kinetics i.e. a constant fraction of
drug undergoes reaction per unit time.
10. t1/2 = 0.693 / K
Equation shows that, in contrast to zero-order process, the half-life of a first-order
process is a constant and independent of initial drug concentration i.e. irrespective of
what the initial drug concentration is, the time required for the concentration to decrease
by one-half remains the same.
Most pharmacokinetic processes viz. absorption, distribution and elimination follow first-
order kinetics.
11. Mixed-Order Kinetics (Nonlinear Kinetics)
A mixture of both first-order and zero-order kinetics is said to follow mixed-order kinetics.
Since deviations from an originally linear pharmacokinetic profile are observed, the rate
process of such a drug is called as nonlinear kinetics. Mixed order kinetics is also termed as
dose-dependent kinetics as it is observed at increased or multiple doses of some drugs.
Nonlinearities in pharmacokinetics have been observed in –
Drug absorption (e.g. vitamin C)
Drug distribution (e.g. naproxen), and
Drug elimination (e.g. riboflavin).
The phenomena is seen when a particular pharmacokinetic process involves presence of
carriers or enzymes which are substrate specific and have definite capacities and can get
saturated at high drug concentrations (i.e. capacity-limited). The kinetics of such capacity-
limited processes can be described by the Michaelis-Menten kinetics.
12. PHARMACOKINETIC PARAMETERS
In practice, pharmacokinetic parameters are determined experimentally from a set of
drug concentrations collected over various times known as data.
Parameters are also called as variables. Variables are of two types –
Independent variables which are not affected by any other parameter, for example time.
Dependent variables, which change as the independent variables change, for example,
plasma drug concentration.
13. PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore
to develop a generalized and simple approach to describe, analyse and interpret the data
obtained during in vivo drug disposition studies. The two major approaches in the
quantitative study of various kinetic processes of drug disposition in the body are
1. Model approach, and
2. Model-independent approach (also called as non-compartmental analysis).
14. Pharmacokinetic Model Approach
A model is a hypothesis that employs mathematical terms to concisely describe
quantitative relationships. Pharmacokinetic models provide concise means of expressing
mathematically or quantitatively, the time course of drug(s) throughout the body and
compute meaningful pharmacokinetic parameters.
Applications of Pharmacokinetic Models –
1. Characterizing the behaviour of drugs in patients.
2. Predicting the concentration of drug in various body fluids with any dosage regimen.
3. Predicting the multiple-dose concentration curves from single dose experiments.
4. Calculating the optimum dosage regimen for individual patients.
5. Evaluating the risk of toxicity with certain dosage regimens.
6. Correlating plasma drug concentration with pharmacological response.
7. Evaluating the bioequivalence/bioinequivalence between different formulations of the same drug.
8. Estimating the possibility of drug and/or metabolite(s) accumulation in the body.
9. Determining the influence of altered physiology/disease state on drug ADME.
10. Explaining drug interactions.
15. Types of Pharmacokinetic Models
Pharmacokinetic models are of three different types –
Compartment models – are also called as empirical models, and
Physiological models – are realistic models.
Distributed parameter models – are also realistic models.
Compartment Models
Compartmental analysis is the traditional and most commonly used approach to
pharmacokinetic characterization of a drug. These models simply interpolate the
experimental data and allow an empirical formula to estimate the drug concentration with
time.
Depending upon whether the compartments are arranged parallel or in a series,
compartment models are divided into two categories —
1. Mammillary model
2. Catenary model.
16. Since compartments are hypothetical in nature, compartment models are based on
certain assumptions –
1. The body is represented as a series of compartments arranged either in series or
parallel to each other, that communicate reversibly with each other.
2. Each compartment is not a real physiologic or anatomic region but a fictitious or virtual
one and considered as a tissue or group of tissues that have similar drug distribution
characteristics (similar blood flow and affinity). This assumption is necessary because if
every organ, tissue or body fluid that can get equilibrated with the drug is considered as a
separate compartment, the body will comprise of infinite number of compartments and
mathematical description of such a model will be too complex.
3. Within each compartment, the drug is considered to be rapidly and uniformly
distributed i.e. the compartment is well-stirred.
4. The rate of drug movement between compartments (i.e. entry and exit) is described by
first-order kinetics.
5. Rate constants are used to represent rate of entry into and exit from the compartment.
18. The number of rate constants which will appear in a particular compartment model is given
by R.
For intravenous administration, R = 2n – 1
For extravascular administration, R = 2n
where n = number of compartments.
Catenary Model
Physiological Models
These models are also known as physiologically-based pharmacokinetic models (PB-PK models).
They are drawn on the basis of known anatomic and physiological data and thus present a more
realistic picture of drug disposition in various organs and tissues. The number of compartments
to be included in the model depends upon the disposition characteristics of the drug. Organs or
tissues such as bones that have no drug penetration are excluded.
19.
20. The physiological models are further categorized into two types –
Blood flow rate-limited models – These models are more popular and commonly used
than the second type, and are based on the assumption that the drug movement within a
body region is much more rapid than its rate of delivery to that region by the perfusing
blood. These models are therefore also called as perfusion rate-limited models. This
assumption is however applicable only to the highly membrane permeable drugs i.e. low
molecular weight, poorly ionised and highly lipophilic drugs, for example, thiopental,
lidocaine, etc.
Membrane permeation rate-limited models – These models are more complex and
applicable to highly polar, ionised and charged drugs, in which case the cell membrane
acts as a barrier for the drug that gradually permeates by diffusion. These models are
therefore also called as diffusion-limited models. Owing to the time lag in equilibration
between the blood and the tissue, equations for these models are very complicated.
21. Noncompartmental Analysis
The noncompartmental analysis, also called as the model-independent method, does
not require the assumption of specific compartment model. This method is, however,
based on the assumption that the drugs or metabolites follow linear kinetics, and on
this basis, this technique can be applied to any compartment model.
The noncompartmental approach, based on the statistical moments theory, involves
collection of experimental data following a single dose of drug. If one considers the
time course of drug concentration in plasma as a statistical distribution curve, then:
MRT = AUMC/AUC
where MRT = mean residence time
AUMC = area under the first-moment curve
AUC = area under the zero-moment curve
MRT is defined as the average amount of time spent by the drug in the body before
being eliminated.
22.
23. ONE-COMPARTMENT OPEN MODEL
(INSTANTANEOUS DISTRIBUTION MODEL)
The one-compartment open model is the simplest model.
1. Elimination is a first-order (monoexponential) process with first-order rate
constant.
2. Rate of input (absorption) > rate of output (elimination).
3. The anatomical reference compartment is plasma and concentration of drug
in plasma is representative of drug concentration in all body tissues i.e. any
change in plasma drug concentration reflects a proportional change in drug
concentration throughout the body.
However, the model does not assume that the drug concentration in
plasma is equal to that in other body tissues.
24. One-Compartment Open Model
Intravenous Bolus Administration
The general expression for rate of drug presentation to the body is:
on)(eliminatioutRate-ity)(availabilinRate
dt
dX
=
XK
dt
dX
Ε−=
25. Estimation of Pharmacokinetic Parameters
Elimination phase can be characterized by 3 parameters—
1. Elimination rate constant
2. Elimination half-life
3. Clearance.
ln X = ln Xo – KE t
Elimination Rate Constant:
X = Xo e–KEt
The above equation shows that disposition of a drug that follows one-compartment
kinetics is monoexponential.
X = Vd C
2.303
tK
ClogClog E
0 -=
26. KE = Ke + Km + Kb + Kl + ......
if a drug is eliminated by urinary excretion and metabolism only, then, the fraction of
drug
excreted unchanged in urine Fe and fraction of drug metabolized Fm can be given as:
E
e
e
K
K
F =
E
m
m
K
K
F =
27. Elimination Half-Life:
E
1/2
K
0.693
t =
T
d
1/2
Cl
V0.693
t =
•Apparent volume of distribution, and
•Clearance.
Since these parameters are closely related with the physiologic mechanisms
in the body, they are called as primary parameters.
C
X
ionconcentratdrugPlasma
bodyin thedrugofAmount
Vd ==
00
0
d
C
dosebolusi.v.
C
X
V ==
28. Clearance is defined as the theoretical volume of body fluid containing drug (i.e.
that fraction of apparent volume of distribution) from which the drug is completely
removed in a given period of time. It is expressed in ml/min or liters/hour.
C
kidneybyneliminatioofRate
ClR =
C
liverbyneliminatioofRate
ClH =
C
organsotherbyneliminatioofRate
ClOthers =
1/2
d
T
t
V0.693
Cl =
29. For drugs given as i.v. bolus
AUC
X
Cl 0
T =
For drugs given e.v.
AUC
XF
Cl 0
T =
30. One-Compartment Open Model
Intravenous Infusion
XKR
dt
dX
E0 −=
)e1(
K
R
X tEK-
E
0
−=
)e1(
Cl
R
)e1(
VK
R
C tEK-
T
0tEK-
dE
0
−=−=
Clearance
rateInfusion
i.e.
Cl
R
VK
R
C
T
0
dE
0
ss ==
31. One-Compartment Open Model
Extravascular Administration
dX/dt = Rate of absorption – Rate of elimination
dt
dX
dt
dX
dt
dX Eev
−=
[ ]tK-tK-
Ea
0a aE
e-e
)K-(K
XFK
X = [ ]tK-tK-
Ead
0a aE
e-e
)K-(KV
XFK
C =
32. At peak plasma concentration, the rate of absorption equals rate of
elimination i.e. KaXa = KEX
[ ]tK-
a
tK-
E
Ead
0a aE
eKeK-
)K-(KV
XFK
dt
dC
+= = Zero
t-K
a
t-K
E
aE
eKeK =
2.303
tK
Klog
2.303
tK
Klog a
a
E
E -- =
KK
)/K(Klog2.303
t
Ea
Ea
max
-
=
maxEtK-
d
0
max e
V
XF
C =
33. Absorption Rate Constant: It can be calculated by the method of residuals.
The technique is also known as feathering, peeling and stripping. It is commonly
used in pharmacokinetics to resolve a multiexponential curve into its individual
components. For a drug that follows one-compartment kinetics and administered
e.v., the concentration of drug in plasma is expressed by a biexponential equation.
[ ]tK-tK-
Ead
0a aE
ee
)K-(KV
XFK
C -=
t-KE
eAC =
2.303
tK
AlogClog E
-=
t-Ka
eACC)C( == τ-
2.303
tK
AlogClog a
-=τ
34. Wagner-Nelson Method for Estimation of Ka
The method involves determination of Ka from percent unabsorbed-time plots and does not
require the assumption of zero- or first-order absorption.
EA XXX +=
t
0dEE [AUC]VKX =
t
0dEdA [AUC]VKCVX +=
∞∞∞
+= 0dEdA [AUC]VKCVX
∞∞
= 0dEA [AUC]VKX
∞∞
+
=
0dE
0dEd
A
A
[AUC]VK
[AUC]VKCV
X
X t
∞
+
=
0E
0E
[AUC]K
[AUC]KC t
100
[AUC]K
[AUC]KC
1100
X
XA
1%ARA
0E
0E
A
+
−=
= ∞∞
t
-
35. Parameters affected Influence when KE is constant Influence when Ka is constant
Smaller Ka Larger Ka Smaller KE Larger KE
Cmax ↓ ↑ ↑ ↓
tmax Long Short Long Short
AUC No Change No Change ↑ ↓
INFLUENCE OF KA AND KE ON CMAX, TMAX AND
AUC
36. URINARY EXCRETION DATA
Criteria for Obtaining Valid Urinary Excretion Data
A significant amount of drug must be excreted unchanged in the urine (at least 10%).
1. The analytical method must be specific for the unchanged drug; metabolites should not interfere.
2. Water-loading should be done by taking 400 ml of water after fasting overnight, to promote diuresis
and enable collection of sufficient urine samples.
3. Before administration of drug, the bladder must be emptied completely after 1 hour from water-
loading and the urine sample taken as blank. The drug should then be administered with 200 ml of
water and should be followed by 200 ml given at hourly intervals for the next 4 hours.
4. Volunteers must be instructed to completely empty their bladder while collecting urine samples.
5. Frequent sampling should be done in order to obtain a good curve.
6. During sampling, the exact time and volume of urine excreted should be noted.
7. An individual collection period should not exceed one biological half-life of the drug and ideally
should be considerably less.
8. Urine samples must be collected for at least 7 biological half-lives in order to ensure collection of
more than 99% of excreted drug.
9. Changes in urine pH and urine volume may alter the urinary excretion rate.
37. Determination of KE from Urinary Excretion Data
1. Rate of excretion method, and
2. Sigma-minus method.
Rate of Excretion Method: The rate of urinary drug excretion dXu/dt is proportional
to
the amount of drug in the body X and written as:
XK
dt
dX
e
u
=
According to first-order disposition kinetics, X = Xo e–KEt
tK-
0e
u E
eXK
dt
dX
=
2.303
tK
XKlog
dt
dX
log E
0e
u
-=
38. Sigma-Minus Method: A disadvantage of rate of excretion method in estimating
KE is that fluctuations in the rate of drug elimination are observed to a high degree
and in most instances, the data are so scattered that an estimate of half-life is
difficult. These problems can be minimized by using the alternative approach
called as sigma-minus method.
tK-
0e
u E
eXK
dt
dX
=
)e(1
K
XK
X tK-
E
0E
u
E
-=
Xu = cumulative amount of drug excreted unchanged in urine at any time t. As time
approaches infinity i.e. after 6 to 7 half-lives, the value e–KE∞ becomes zero and therefore
the cumulative amount excreted at infinite time Xu ∞ can be given by equation
K
XK
X
E
0e
u =∞
t-K
uuu
E
eXXX ∞∞
=-
2.303
tK
Xlog)X(Xlog E
uuu -- ∞∞
=
39. (Xu∞ – Xu) = amount remaining to be excreted i.e. ARE at any given time. A
semilog plot of ARE versus t yields a straight line with slope -KE/2.303. The
method is, therefore, also called as ARE plot method. A disadvantage of this
method is that total urine collection has to be carried out until no unchanged drug
can be detected in the urine i.e. upto 7 half-lives, which may be tedious for drugs
having long t½.