Presented by Terry Blaschke, M.D.at the meeting of the

Clinical Pharmacology Subcommittee of the

Advisory Committee for Pharmaceutical Science

Computers and Biomedical Research 1972;5:441-59

Ann Intern Med 1975;82:619-27

Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data.

Sheiner LB, Beal SL.

Individual pharmacokinetic par parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual variability, and residual intraindividual variability plus measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters are estimated either by fitting all individual's data together as though there was no individual kinetic differences (the naive pooled data approach), or by fitting each individual's data separately, and then combining the individual parameter estimates (the two-stage approach). A third approach, NONMEM, takes a middle course between these, and avoids shortcomings of each of them…This performance is exactly what is expected from theoretical considerations and provides empirical support for the use of NONMEM when estimating population pharmacokinetics from routine type patient data.

J Pharmacokinet Biopharm 1980;8:553-71.

Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine.

Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J.

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect.

Clin Pharmacol Ther 1979;25:358-71

Three Compartment Model plus an “Effect Site”Three Compartment Model plus an “Effect Site”

I

V 2k 12 V 1

k 13 V 3

Rapidly Equilibrating Compartment

k 21Central

Compartmentk 31

Slowly EquilibratingCompartment

k 10

Effect Site

V e

Drug Administration

k 1e

k e0

Clinical Pharmacokinetics 1981;6:429-53

Clin Pharmacol Ther 1989;46:63-77

Drug RegimensEXPOSURE

INPUT PROFILE

Drug Effects(EFFICACY/TOXICITY)

PatientCharacteristics

agekidney functionseverity of illness

Benefit:Risk Response Surface

(Courtesy of Lewis Sheiner)

**

RCT

Br J Clin Pharmacol, 2000;54:203–11

Annu Rev Pharmacol Toxicol 2000;40:67-95

FDA SERVICE & ADVISORY BOARDS -

• 1987- Expert Consultant to the FDA; Center FOR Drug Evaluation and Research (formerly Center for Drugs and Biologics), Rockville, MD• 1991-94 Member, Antiviral Drugs Advisory Committee, CDER,

FDA, Rockville, MD• 1997 Member, Expert panel: Guidance on Population PK/PD,

CDER, FDA, Rockville, MD.• 1998- Member, Expert Panel: Individual and Population Bioequivalence, CDER, FDA, Rockville, MD• 1999- Member, Expert Panel: Exposure-Response Guidance,

CDER, FDA, Rockville, MD• 2002- Member, Clinical Pharmacology Subcommittee

VISITING FACULTY SUPERVISED:VISITING FACULTY SUPERVISED:Brian Whiting, MD Adrian Dunne, PhD (with SL Beal)Robert Laplanche, PhD Margaret Lynn McFayden, PhDPascal Girard, PhD Margareta Hammarlund-Udenaes, PhDXiaojaian Zhou, PhD Jeffrey Koup, PhD

POST DOCTORAL SCHOLARS POST DOCTORAL SCHOLARS SUPERVISED:SUPERVISED:

Carl Peck, MD Diana Nicoll, MD, PhDHillel Halkin, MD Samuel Vozeh, MDRenato Galeazzi, MD Donald Stanski, MDPeter Ravenscroft, MD David Wicker, MDNestor Sanchez, MD Thaddeus Grasela, PharmDEliane Fuseau, PhD Johan Gabrielson, PhDNicholas Holford, MSc, MB, CHB Jashvant Unadkat, PhDLawrence Wheeler, MD, PhD Stanley Perkins, MDHerve Porchet, MD Nancy Sambol, PharmDFerenc Bartha Davide Verotta, PhDYukiya Hashimoto, PhD Beny Mozes, MDShi Jun, MD Ruediger Port, MDDominik Uehlinger, MD Leslie Lenert, MD (Stanford)Kazumasa Aizawa, PhD Inaki Fernandez-Toconiz, PhDMats Karlsson, PhD Karen Fattinger-Bachmann, MD Jacob Mandema, PhD Janet Wade, PhD (with N. Sambol)Kyungsoo Park, PhD Jean-Michel Gries, PhD Atsunori Kaibara, PhD Saraswati Kinkare, PhD Christine Veyrat, PhD Eugene Cox, PhDYoshitaka Yano, PhD Ikuko Yano, PhD (with S. Beal)Niclas Jonsson, PhD Jianfeng Lu, PhDMarc Pfister, MD Line Labbe, PhDDolors Soy, PhD Micha Levy, PhD