ECOLE NATIONALE VETERINAIRE T O U L O U S E Rationale for the effective use of pharmacokinetics and pharmacodynamics in drug development P.L. Toutain Update: 09/10//2010

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

PHARMACOLOGY Clinical pharmacology Pharmacokinetics Pharmacodynamics Study of drug in a clinical context Action of animal on drug Pharmacodynamics Action of drug on animal

Clinical trials vs. PK/PD trials

Dose titration PK/PD Black box Dose Response PK PD Response surrogate Plasma concentration

Dose effect vs. concentration effect relationship External dose EFFECT Internal dose DOSE AUC = (Dose/Cl) Less variance must be expected in the AUC/effect than in the dose/effect relationship

dose-effect vs. exposure- effect relationship for GnRH LH response Monnoyer et a.l J vet pharmaco ther 2004

Acute toxicity of anticancer drugs human versus mouse Dose Ratio External dose AUC Ratio Internal dose Frequency

Digoxin levels in toxic and nontoxic patients * From smith TW and haber E. J clin invest 1970;49:2377-86.

The concentration principle in drug development: Extrapolations From in vitro to in vivo From experimental to target species

PK/PD: in vitro vs. in vivo Response Plasma concentration Body Extrapolation in vitro  in vivo In vitro Medium concentration effet Test system

PK/PD for antibiotics: extrapolation from in vitro to in vivo Bactericidal effect Plasma AB concentration Body pathogen In vitro Medium AB concentration Agar/ MH Pathogen MIC Killing rate

The concentration principle in drug development: mechanistic approach

PK/PD: mechanistic approach Response Dose Plasma concentration Response Dose Plasma concentration Drug receptor interaction Transduction System specificity Drug specificity, affinity & intrinsic efficacy

The concentration principle in drug development Drug action is mediated via the time course of drug concentration at the site of action easy to demonstrate in vitro also true in vivo

The concentration principle in drug development The direct assessment of drug concentration at the actual site of action is seldom possible but: the drug concentration in plasma often bears a proportional relation and plasma concentrations can be used instead of site concentration

Indications for measuring blood levels To determine an optimal dosage regimen Dose Dosage interval Conditions of administration Route; site etc To guide dose adjustment

Dose vs. plasma concentration profile as independent variable Clearance Time X Mass (no biological information) Concentration profile (biological information)

PK vs. PD variability i.e. the 2 main sources of variability

PK is a critical step in understanding drug response and improving efficacy: Why ? Many factors of variation Interspecific Absorption Distribution Metabolism Elimination Dose Concentration Factors of variation more limited Species Diet Age Gender Diseases Environment (husbandry,…) EFFECTS

PK and PD variability well documented PK PD Effect BODY Dose Receptor Plasma concentration well documented species food age sex diseases Generally ignored but usually more pronounced than PK variabilities (for a given species)

PK/PD variability for anti-inflammatory drugs Coefficient of variation (%) PK PD Clearance Vss EC50 EC50 antipyretic anti-inflammatory Nimesulide 17 20 49 62 Tolfenamic Ac. 28 9.5 47 48 Prednisolone 12 15 49 T. Haake, 1997

Definition of the main pharmacodynamic drug properties Efficacy Drug action, drug effect, drug response efficiency Potency Power Sensitivity Selectivity Specificity

The 3 structural parameters of the dose-effect relationship Emax ED50 slope 1 1 Emax 1 1 2 2 Emax 2 2 shallow steep ED501 ED502 Sensitivity Potency Efficacy Range of useful concentrations Selectivity

Efficacy vs. potency and selectivity Efficacy, potency and selectivity therapeutic effect side effect A B 100 Effect 80 Concentration A more potent than B A = B for efficacy B is preferable to A in a clinical context for its selectivity

PK/PD variabilitiy Consequence for dosage adjustment Effect Dose BODY Receptor Plasma concentration Clinical covariables disease severity or duration pathogens susceptibility Kidney function Liver function ... Population approach

How to document variabilities POPULATION PK/PD

Kinetic population vs. classical approach Few (healthy) laboratory intensive yes narrow Population Many (patient) hospital sparse no no (but documented) large Subjects Location of study Sampling Subject homogeneity Controlled variable Inference space

What is the usefulness of PK Drug discovery and development Drug submission Drug prescription A requirement for regulatory affairs A scientific tool R & D Drug monitoring Guidelines Scientific critical mass of the company Human medicine Very basic Can be very sophisticated

Usefulness of PK 1-Drug prescription

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 ?

Effect of adherence rate on outcome in HIV infected patients From: Paterson DL, et al. Ann Intern Med 2000;133:21-30.

Usefulness of PK 2-Drug discovery

Drug discovery and PK Historically poor PK (40%) but much better now 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

Why compounds fail or slow down in development

Pharmacokinetics and combinatorial chemistry Chemistry (thousands of compounds per day) High screen throughput using molecular and cellular systems Selection of putative active compound Are these compounds able to become a drug Yes, if PK properties are appropriate

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 process is accepted

Drug discovery strategies Hit screening - screen large compound libraries to find molecule with a specific biological response and having a high potency Lead generation/ optimization - application of structure-activity relationship (SARs) to improve hits and produce leads and after optimization, to produce candidate

Position of in vitro and in vivo PK screen in the lead generation / optimization phases of the drug discovery process

Hits Leads optimized leads Potency/selectivity screening Hits Leads optimized leads Re-synthesis In-vitro DMPK screens In vivo DMPK screens Development candidate Roberts S.A. Current opinion, Drug Disc. Dev. 2003,6: 66-80

Hierarchical in vitro screening sequences Physiochemical analysis; measured or computed New compound(s) 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 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

Clearance Renal Hepatic Metabolic Biliary IR CYP450 Others Polymorphism 1A2;2C9;2C19;2D6;3A4 Amino-acid Glucuronide CAR Inhibition Sulfate Induction AHR PXR

Pharmacokinetics and combinatorial chemistry PK (clearance determination) is the bottleneck cocktail approach and cassette dosing Objectives 200 compounds per week for 2 scientists

PK as a scientific tool 1- Drug discovery 2- Preclinical development drug or prodrug design rational screening of drug and prodrug 2- Preclinical development support for toxicology support for pharmacodynamics Dose titration Interspecific prediction New formulation 3- Clinical development

The drugability Some general rules to understand the differences between a pharmacologically active compound and a future marketed drugs synthetic route, molecular weight , solubility, lipophilicity, logP, rule of five, bioavailability, efficacy, specificity, toxicity, blood brain barrier

Molecular weight WDI: 3800 - 4100 drugs with calculable properties

Possible Impacts of MW Size or molecular weight of a potential drug affects: stability, ease of synthesis? solubility, transport across membranes bioavailability Biliary excretion (interspecific differences) Safety (antigenicity) success in clinical trials FDA approval!

Lipophilicity and partitioning coefficient (logP & logD) As a definition logP refers to the neutral form of the compound.

Lipophilicity - Hydrophilicity Critical values for LogP > 6 : poor water solubility Bad dissolution Too long residence time in lipidic phases Drug Discovery Today, 1996, 1: 179

Lipophilicity - Hydrophilicity Critical values for LogP -3 à 0 : good hydrophilicity and paracellular passage Slower rate of absorption than for the transcellular pathway (limited absorption area) Influence of the MW (if too high, absorption is decreased) < -3 : too polar and impossible to cross a membrane Drug Discovery Today, 1996, 1: 179

3-Regulatory pharmacokinetics Usefulness of PK 3-Regulatory pharmacokinetics

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

Regulatory pharmacokinetics Safety Efficacy Clinical trials PD PK properties Quality Proofs are independent The clinical trial is not the "pathognomonic" proof of drug efficacy and safety

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

In a company, is PK conducted as : A regulatory requirement or For rationale drug development

If PK is scientifically conducted 10 critical PK and PD parameters should be determined for each new drug

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

Hierarchy of pharmacokinetic parameters R & D Independent Have a physiological meaning Clearance, distribution Regulatory affairs Hybrid Only descriptive t 1/2, Cmax, Tmax