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ECOLE NATIONALE VETERINAIRE TOULOUSE Rationale for the effective use of pharmacokinetics and pharmacodynamics in drug development Update: 09/10//2010 P.L. Toutain 1 Objective of the presentation • To show non-kineticists that PK can be a very useful tool to document drug safety and efficacy • To understand the meaning and utility of the main PK parameters 2 PHARMACOLOGY Pharmacokinetics Action of animal on drug Clinical pharmacology Study of drug in a clinical context Pharmacodynamics Action of drug on animal 3 Clinical trials vs. PK/PD trials 4 Dose titration Dose Response Black box PK/PD PK PD Response surrogate Dose Plasma concentration 5 Dose effect vs. concentration effect relationship EFFECT External dose DOSE EFFECT Internal dose AUC = (Dose/Cl) Less variance must be expected in the AUC/effect than in the dose/effect relationship 6 Acute toxicity of anticancer drugs human versus mouse AUC Ratio Internal dose Frequency Dose Ratio External dose 14 14 12 12 10 10 8 8 6 6 4 4 2 2 0 0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4 0 0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4 8 Digoxin levels in toxic and nontoxic patients Non toxic (131) Toxic (48) * From smith TW and haber E. J clin invest 1970;49:2377-86. 9 The concentration principle in drug development: Extrapolations • From in vitro to in vivo • From experimental to target species 10 PK/PD: in vitro vs. in vivo In vivo Plasma concentration Body Response Extrapolation in vitro in vivo In vitro Medium concentration effet Test system 11 The concentration principle in drug development: mechanistic approach 13 PK/PD: mechanistic approach PK/PD PK PD Response Dose Plasma concentration Dose Response Plasma concentration Drug receptor interaction Transduction System specificity Drug specificity, affinity & intrinsic efficacy 14 Dose vs. plasma concentration profile as independent variable Dose Mass (no biological information) Dose X F% Clearance Time Concentration profile (biological information) 18 PK vs. PD variability i.e. the 2 main sources of variability 19 PK and PD variability PK Dose PD BODY Receptor Effect Plasma concentration well documented – – – – – species food age sex diseases Generally ignored but usually more pronounced than PK variabilities (for a given species) 21 PK/PD variability for antiinflammatory drugs Coefficient of variation (%) PK PD Clearance Vss EC50 EC50 antipyretic anti-inflammatory Nimesulide Tolfenamic Ac. Prednisolone T. Haake, 1997 17 28 12 20 9.5 15 49 47 62 48 49 22 Definition of the main pharmacodynamic drug properties • Efficacy – Drug action, drug effect, drug response – efficiency • Potency – Power • Sensitivity • Selectivity • Specificity 23 The 3 structural parameters of the dose-effect relationship 1 Emax 1 slope ED50 Emax 2 2 Emax 2 1 1 2 shallow steep ED501 ED502 Efficacy Potency Sensitivity Range of useful concentrations Selectivity 24 Efficacy vs. potency and selectivity • Efficacy, potency and selectivity Effect A therapeutic effect side effect B 100 80 Concentration A more potent than B A = B for efficacy 25 B is preferable to A in a clinical context for its selectivity PK/PD variabilitiy • Consequence for dosage adjustment PK Dose PD BODY Receptor Effect Plasma concentration Kidney function Liver function ... Clinical covariables • disease severity or duration • pathogens susceptibility Population approach 26 Kinetic population vs. classical approach Classical Population • Subjects Few (healthy) Many (patient) • Location of study laboratory hospital • Sampling intensive sparse • Subject homogeneity yes no • Controlled variable yes no (but documented) • Inference space narrow large 28 What is the usefulness of PK Drug discovery and development Drug submission A scientific tool R&D Scientific critical mass of the company Can be very sophisticated Drug prescription A requirement for regulatory affairs Drug monitoring Guidelines Human medicine Very basic 29 Usefulness of PK 1-Drug prescription 30 Drug candidates for Therapeutic Drug Monitoring (TDM) • Low therapeutic index • No physiologic or therapeutic endpoints to guide dosage • Pharmacokinetics vary widely between individuals • Need to monitor adherence ? 31 Effect of adherence rate on outcome in HIV infected patients VIROLOGIC FAILURE RATE (%) 80 60 40 20 0 ≥ 95% 80% - 94% < 80% ADHERENCE RATE From: Paterson DL, et al. Ann Intern Med 2000;133:21-30. 32 Usefulness of PK 2-Drug discovery 33 Drug discovery and PK • The success rate of New Chemical Entities (NCE) is low (1/5000) • The main reasons for failure were : – unacceptable clinical efficacy –Historically poor PK (40%) but much better now 34 Why compounds fail or slow down in development 35 Drug discovery strategies • Researchers have concentrated on maximizing potency and selectivity (specificity) against a biological target but • a good candidate requires a balance of potency, safety and PK properties now: • drug metabolism and PK in drug discovery 37 process is accepted Hierarchical in vitro screening sequences New compound(s) Physiochemical analysis; measured or computed In vitro binding against target receptor In vitro binding against selectivity receptors Functional activity against target receptor In vitro intrinsic clearance in hepatocytes In vitro permeability in Caco-2 cells In vitro protein binding In vivo pharmacokinetic and pharmacodynamic evaluation 41 Roberts S.A. Current opinion, Drug Disc. Dev. 2003,6: 66-80 Predictive models ADME processes van de Waterbeemd & Gifford, Nature Reviews Drug Discovery 2, 192, 2003 42 Clearance Renal Hepatic Metabolic IR CYP450 Polymorphism Biliary Others 1A2;2C9;2C19;2D6;3A4 Amino-acid Glucuronide Inhibition CAR Induction Sulfate AHR PXR 43 Pharmacokinetics and combinatorial chemistry • PK (clearance determination) is the bottleneck cocktail approach and cassette dosing • Objectives – 200 compounds per week for 2 scientists 44 Possible Impacts of MW Size or molecular weight of a potential drug affects: 1. stability, ease of synthesis? 2. solubility, transport across membranes 3. bioavailability 4. Biliary excretion (interspecific differences) 5. Safety (antigenicity) 6. success in clinical trials 7. FDA approval! 48 Usefulness of PK 3-Regulatory pharmacokinetics 52 Regulatory pharmacokinetics • Purpose – Necessity to understand the role of regulatory authorities – The role of the authorities is to ensure that marketed drug products are safe and effective – The authority requires basic PK information to understand the features of the drug and factor variation 53 Regulatory pharmacokinetics • Guideline vs. science driven PK – the PK guidelines were written to provide regulatory people with the minimal information required to make a judgment and not to provide companies with an optimal drug development procedure – Some companies have forgotten the true purpose of PK studies and too often PK data appear to have been generated with a "checklist" for regulatory authorities in mind rather than a scientific approach to efficacy 55 In a company, is PK conducted as : A regulatory requirement or For rationale drug development 56 If PK is scientifically conducted 10 critical PK and PD parameters should be determined for each new drug 57 Hierarchy of pharmacokinetic parameters R&D • Clearance • Effective concentration range • Extent of bioavailability • Fraction of the available dose excreted unchanged • Blood / plasma concentration ratio • Half-life • Toxic concentration • Extent of protein binding • Volume of distribution • Rate of availability Regulatory • Absorption • Distribution • Metabolism • Elimination Benett, 1993 58 Hierarchy of pharmacokinetic parameters R&D Regulatory affairs • Independent • Hybrid • Have a physiological meaning • Only descriptive • Clearance, distribution • t 1/2, Cmax, Tmax 59