For many drugs, the gastrointestinal absorption rate, but not the. Flash version 2 is required for showing this movie. Apply the basic principles of interpretation of serum drug concentrations in practice. Compare by statistical methods, two or more different pharmacokinetic models for fitting a set of pharmacokinetic data and determine the best model. Nonlinear pharmacokinetics is the characteristic of drugs that briefs that the absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. Kinetics resulting from saturable drug transfer, leading to variation of the standard kinetic parameters with drug concentration. Drug administration often the goal is to attain a therapeutic drug concentration in plasma from which drug enters the tissue therapeutic window between toxic concentration and minimal effective concentration. Causes of non linear pharmacokinetics slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. Thp pharmacokinetics obeys a non linear profile 7, with serum concentration sometimes increasing higher than predicted after administration, due to some mechanisms that are currently not fully. Pharmacokinetics from ancient greek pharmakon drug and kinetikos moving, putting in motion. Pharmacokinetics describes how the body affects a specific xenobioticchemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body e. Besides saturation of plasma proteinbinding or carriermediated systems, drugs may demonstrate nonlinear pharmacokinetics due to a pathologic alteration.
Under nonlinear kinetics, the rate of elimination is not concentration dependent, but is a constant. Because there was no urinary excretion fe of compound a. Non linear drugs n94 linear drugs n345 p linear pharmacokinetic models using simple firstorder kinetics to describe the course of drug disposition and action. Pharmacokinetics and pharmacodynamics, 4th edn, 2011 hepatic metabolism metabolism vmax. Jan 22, 2014 contents of the powerpoint on non compartmental pharmacokinetics include. In some cases, dosage adjustment must be made to compensate for the increase, and the possibility that the degree of induction may be dose or concentrationdependent must be kept in mind. Pk nonlinear pharmacokinetics medicine flashcards quizlet. Binding kinetics of drug there are many causes of nonlinear elimination. These linear models assumed that the pharmacokinetic parameters for a drug would not change when different doses or multiple doses of a drug were given. Non linear pharmacokinetics pharmacokinetics enzyme. Drug which do not follow first order kinetics shows non linear or mixed order kinetic. Here clearance is inversely related to the concentration. As shown in table 101, various causes of nonlinear pharmacokinetic behavior. Venlafaxine and odv exhibited linear kinetics over the dose range of 75 to 450 mgday product information 0 100 200 300 400 500 0 200 400 600 800 1200 0 100 200 300 400 500 600.
Linear pharmacokinetics list of high impact articles ppts. Mar 26, 2018 under non linear kinetics, the rate of elimination is not concentration dependent, but is a constant. As shown in table 101, various causes of nonlinear pharmacokinetic behavior are theoretically possible. In order to investigate the possibility of increasing the numerical stability and the rate of convergenceofthenlmealgorithm,agradientattribute is included by simultaneous solution to the associated sensitivity equations to be used in the gaussnewton non linear leastsquares optimizationalgorithm.
The pharmacokinetic behavior of foreign substances that are completely or partially eliminated via metabolism by saturable enzyme systems is analyzed. The absorption, distribution, and excretion of drugs objectives after studying this chapter, the reader should be able to. Mar 18, 2014 drug dosing non linear pharmacokinetics part 1 shankar lanke. The halflife will remain constant, irrespective of how high the concentration. These are useful for most of the situations, though assumptions of modeling are involved. The non linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated.
Pkadme in drug discovery oioverview pharmacokinetics, absorption, distribution, metabolism, elimination pharmacodynamics why these are important in early research, target validation and discovery programs when should they be determined early in the process examples. With some drugs, increased doses or chronic medication can cause deviations from the linear. Basic kinetic parameters, possible causes of noninduction, nonlinear binding, and non linearity of pharmacological responses. Nonlinear pharmacokinetics, as opposed to the more com monly observed.
Nonlinear pharmacokinetics can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. Figure a shows concentrationtime data in a linear scale and illustrates how the auc from time 0 to infinity is calculated. Phar 7633 chapter 21 nonlinear pharmacokinetic models. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. As shown in table 91, various causes of nonlinear pharmacokinetic behavior are theoretically possible. A major route of excretion is through the bile, where unchanged sns595, a glucuronide metabolite, and two des methyl metabolites are detected. Causes of non linearity in pharmacokinetics pdf slideshare. Difference between linear and non linear pharmacokinetics. The substances of interest include any chemical xenobiotic such as. Causes of non linearity find, read and cite all the research you need on researchgate.
Concepts of linear and nonlinear pharmacokinetics, michaelismenton kinetics characteristics. Therefore, the bulk of lmwh is excreted via the renal nonsaturable and linear mechanism. Explain the meaning of the terms absorption, distribution, metabolism, and excretion. The clinical pharmacology of methadone induction erin brooke morton, bbiotechhons discipline of pharmacology school of medical sciences faculty of health sciences university of adelaide january 2007 a thesis submitted for the degree of doctor of philosophy. Drug dosing non linear pharmacokinetics part 1 shankar lanke. Apply onecompartment pharmacokinetics to describe steadystate serum drug concentrations following oral slowrelease dosing. Phenytoin needs to be given twice or 3 times daily because it has a halflife of about 12 hours.
Causes of non linear pharmacokinetics linkedin slideshare. Oatp1b1expressing cells, oatp1b3 expressing cells, or control cells were incubated with 0. Drug which do not follow first order kinetics shows nonlinear or mixed order kinetic. Jul 09, 20 3,4methylenedioxymethamphetamine mdma is a widely abused illicit drug that can cause severe and even fatal adverse effects. Ferry received march 15, 1984final november 7, 1984. Difference between linear and non linear pharmacokinetics linear pharmacokinetics change in plasma concentration due to adme process is proportional to dose of drug administered single or multiple follow first order kinetics semilog plot for concentration vs time is super imposable principle of superimposition no change in. Clinical pharmacokinetic studies of pharmaceuticals this document is an informal translation of the official text that was promulgated in japanese on 1 june 2001 by ministry of health, labour, and welfare and is intended for use as a reference in conducting clinical pharmacokinetic studies of pharmaceuticals. Pdf evidence for nonlinear pharmacokinetics of oxytocin. Linear pharmacokinetics dose independent follows firstorder rate kinetics non linear pharmacokinetics dose dependent follows mixture of first and zeroorder rate kinetics 6. Contents of the powerpoint on non compartmental pharmacokinetics include. This is because it is a capacity limited reaction in which the enzyme or its cofactor is not in limitless supply. Linear and nonlinear kinetics of drug elimination i.
As shown in table 91, various causes of nonlinear pharmacokinetic behavior are. The factors causing nonlinear pk are categorized into dose ca pacity and time timedependent inhibitioninduction of enzyme or. No dose adjustment dose adjustment negative results. Binding to plasma proteins will increase the rate of passive absorption by maintaining the concentration gradient of free drug. Nonlinear kinetics is usually due to saturation occuring in one of the pharmacokinetic mechanisms.
Phar 7633 chapter 21 nonlinear pharmacokinetic models scheme or diagram diagram 21. Principles of nonlinear pharmacokinetics semantic scholar. Sns595 liver microsomal stability the potential for sns595 mediated induction of. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. Nonlinear pharmacokinetics of mdma three pharmacokinetic studies in a controlled setting that pharmacokinetics of mdma.
B drug serum concentrations decrease in a straight line when plotted on a log concentrationtime graph. Nonlinear pharmakokinetics linear pharmacokinetics. Nonlinear pharmacokinetics applied biopharmaceutics. The metabolism of mdma involves ndemethylation to 3,4methylenedioxyamphetamine mda figure 1. Nonlinear pharmacokinetics list of high impact articles. Pdf evidence for nonlinear pharmacokinetics of oxytocin in. Elimination of drug does not follow simple firstorder kineticsthat is, elimination kinetics are nonlinear. Nonlinear pharmacokinetics in other words, time or dose dependences in pharmacokinetic parameters can arise from factors associated with absorption, firstpass metabolism, binding, excretion and biotransformation. Causes of nonlinearity in pharmacokinetics presented by. A drug serum concentrations decrease in a straight line when plotted on a concentrationtime graph. Apply onecompartment pharmacokinetics to single and multiple dosing following the intravenous and oral administration of drugs. Enzyme saturation % 10 20 30 40 50 60 70 80 90 100 ethanol 0. With some drugs, increased dose or chronic medication can cause deviation from the linear pkinetics.
Pharmacokinetics dose dependent process presented by. C steadystate drug serum concentrations change proportionally to dose. The pharmacokinetic parameters of lmwh are independent of the dose pharmacokinetics of heparin and low molecular weight heparin 539 injected. This has been further included four subjects have been published to date 69. However, the elimination halflife might decrease due to selfinduction of liver. Principles of nonlinear pharmacokinetics researchgate. Nonlinear mixedeffects pharmacokineticpharmacodynamic. Linear pharmacokinetics,the characteristic of drugs that indicates the instantaneous rate of change in drug concentration depends only on the current concentration. Reduced pk study n vs esrd pts not on dialysis full pk negative results positive results. Drug binding many drugs will bind strongly to proteins in the blood or to food substances in the gut. For a drug with linear pk, we would expect that a 2fold increase in dose would result in a 2fold increase in drug exposure. Pharmacokinetics pk what the body does to the drug pharmacodynamics pd what the drug does to the body an outstanding overview.
In this the pkinetic parameter for a drug would not change when different doses or multiple doses of a drug is given. In a drug with non linear kinetics, doubling the dose will double the concentration. A modern view of pharmacokinetics deep blue university of. Particularly useful for the applications of clinical pharmacokinetics. So, it is called as dose dependent pharmacokinetic. A mixture of both first order and zero order kinetics is called as mixed order kinetics. List two physiologic factors that can alter each of the processes of absorption, distribution, and excretion. In some cases, the kinetics of a pharmacokinetic process change from predominantly first order to predominantly zero order with increasing dose or chronic medication. In order to investigate the possibility of increasing the numerical stability and the rate of convergenceofthenlmealgorithm,agradientattribute is included by simultaneous solution to the associated sensitivity equations to be used in the gaussnewton nonlinear leastsquares optimizationalgorithm. Nonlinear pharmacokinetics 1 pharmacokinetics enzyme.
Mar 26, 2018 linear pharmacokinetics dose independent follows firstorder rate kinetics nonlinear pharmacokinetics dose dependent follows mixture of first and zeroorder rate kinetics 6. Difference between linear and non linear pharmacokinetics linear pharmacokinetics change in plasma concentration due to adme process is proportional to dose of drug administered single or multiple follow first order kinetics semilog plot for concentration vs time is super imposable principle of superimposition no change in f, ka. Autoinduction causes an increase in clearance with long term administration. Clinical pharmacokinetic studies of pharmaceuticals.
Drug dosing non linear pharmacokinetics part 1 youtube. The process of drugs adme involve enzymes or carriermediated systems. Figure b shows the same data in a semilogarithmic scale. General integrated equations are derived which describe the time course of the plasma concentration under the assumption of a saturable enzyme system according to michaelismenten kinetics in combination with normal firstorder elimination. Tdm of drugs with nonlinear pharmacokinetics aka saturable or zero order. A modern view of pharmacokinetics must include both linear and non linear systems. General integrated equations are derived which describe the time course of the plasma concentration under the assumption of a saturable enzyme system according to michaelismenten kinetics in combination with normal firstorder. An example identified a new compound for memory loss.
Enzyme induction decrease in peak plasma concentration. Linear pharmacokinetics dose independent follows firstorder rate kinetics nonlinear pharmacokinetics dose dependent follows mixture of first and zeroorder rate kinetics 6. Pharmacokinetics the study of absorption, distribution, metabolism and excretion of drugs and their relationship to pharmacological response or it is the science which deals with the study of biological fate of drug and its metabolites during its sojourn in human body with the help of mathematical models. Definition non linear pharmacokinetics implies deviations in the rate of change in the amount or concentration of a drug in any physiological or experimental system whole body,organ or compartment from first order kinetics in a dose or concentrationand or a time dependent manner. The reason for the nonlinearity is related to the clearance of the drug from the body. Nonlinear pharmacokinetics 1 pharmacokinetics enzyme kinetics. Evidence for nonlinear pharmacokinetics of oxytocin in anesthetized rat article pdf available in journal of pharmacy and pharmaceutical sciences 114. Linear pharmacokinetics list of high impact articles. Professor of clinical pharmacology, flinders university of south australia, adelaide. Principles of nonlinear pharmacokinetics reza mehvar1 school of pharmacy, texas tech university health sciences center, 0 south coulter street, amarillo tx 79106 prologue nonlinear pharmacokinetics, as opposed to the more commonly observed linear pharmacokinetics, is a topic of discussion in most basic pharmacokinetics courses offered to.
C1 time profile is regarded as expressions of exponents c1 time profile is regarded as statistical distribution. Nonlinear pharmacokinetics of mdma ecstasy in humans. Introduction to noncompartmental pharmacokinetic approach differences between compartment and noncompartment models concepts of noncompartmental model statistical moments theorymean residence time different pharmacokinetic parameters in noncompartment model noncompartment. Analysis of nonlinear pharmacokinetics of a highly albuminbound. Pdf on apr 23, 2018, nazneen sultana and others published non linear pharmacokinetics.
Introduction to noncompartmental pharmacokinetic approach differences between compartment and noncompartment models concepts of noncompartmental model statistical moments theorymean residence time different pharmacokinetic parameters in noncompartment model noncompartment pharmacokinetics is a new approach devised to. Capacity limited metabolism due to enzyme or cofactor saturation eg. Describe the differences between manual noniterative curve fitting and computerized nonlinear weighted least squares regression. If you continue browsing the site, you agree to the use of cookies on this website. Giltinan, in encyclopedia of biostatistics, 2nd edition 6. Phar 7633 chapter 21 non linear pharmacokinetic models scheme or diagram diagram 21. C steadystate drug serum concentrations change proportionally to.