Case History -Use of ADME Studies for Optimization of Drug Candidates

Liang-Shang Gan, Frank W. Lee, Nelamangala Nagaraja, Ping Li, Jason Labutti, Wei Yin, Cindy Xia, Hua Yang, Vinita Uttamsingh, Chuang Lu, Sandeepraj Pusalkar, J. Scott Daniels, Ron Huang, Mark Qian, Jing-Tao Wu, Kym Cardoza, Suresh K. Balani, and Gerald T. Miwa

Drug Metabolism and Pharmacokinetics Drug Safety and Disposition, Millennium Pharmaceuticals, Inc. 40 Landsdowne Street Cambridge, MA 02139, USA

Table of Contents

Introduction 84

Discovery Assays by Stage (DABS) 86 Pharmacokinetic Optimization from "Hit-to-Lead" (HTL) to "Lead Optimization" (LO) Clearance (CL)

A. Hepatic clearance 87

B. Extrahepatic clearance 88 Volume of Distribution (Vd)

A. Brain uptake 89

B. RBC partition 90 Human Pharmacokinetics (PK) and Dose Projections 91 Proof of Concept (POC) in Pharmacology 92

A. Discrete vs. cassette PK studies 93

B. Inhibition of CYP activities by ABT 94 Acknowledgements 95 References 96

List of Abbreviations

ABT 1-aminobenzotriazole

ADME absorption, distribution, metabolism and excretion

AUC area under the concentration curve

CLhep hepatic clearance

CLp plasma clearance

CLr renal clearance

Cmax maximum plasma concentration

CNS central nerve system

CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes

CYP cytochrome P-450

DC development candidate

DMPK drug metabolism and pharmacokinetics

DABS discovery assays by stage

DC development candidate

DDI drug drug interaction

EC50 concentration gives 50% of maximum effect

HTS high throughput screen

HTL hit-to-lead

IC 50 concentration causes 50% of maximum inhibition

IP intraperitoneally

IV intravenously

IVIVC in vitro in vivo correlation ka absorption rate constant

LO lead optimization

MEC minimum effective concentration

MTD maximum tolerable dose

MOA mode of action

NOAEL no adverse effect level

NOEL no effect level pADME predictive ADME

Pgp P-glycoprotein

PPB plasma protein binding

Papp apparent permeability coefficient

POC proof of concept

RBC red blood cell t1/2 half-life

TK toxicokinetics

Vd volume of distribution

Vss volume of distribution at steady state.

Keywords discovery assays by stage (DABS); absorption, distribution, metabolism and excretion (ADME); drug metabolism and pharmacokinetics (DMPK); hit to lead (HTL); lead optimization (LO); Drug Drug Interaction (DDI), maximum tolerable dose (MTD); no adverse effect level (NOAEL); no effect level (NOEL), therapeutic index, and safety window.

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