Contributors

xi

Preface

xv

Acknowledgments

xix

1

Pharmacometrics: Impacting Drug Development and Pharmacotherapy   Paul J. Williams and Ene I. Ette

1

PART I

GENERAL PRINCIPLES

2

General Principles of Programming: Computer and Statistical   Sastry S. Isukapalli and Amit Roy

25

3

Validation of Software for Pharmacometric Analysis   Gary L. Walk

53

4

Linear, Generalized Linear, and Nonlinear Mixed Effects Models   Farkad Ezzet and José C. Pinheiro

103

5

Bayesian Hierarchical Modeling with Markov Chain Monte Carlo Methods   Stephen B. Duffull, Lena E. Friberg and Chantaratsamon Dansirikul

137

6

Estimating the Dynamics of Drug Regimen Compliance   Ene I. Ette and Alaa Ahmad

165

7

Graphical Displays for Modeling Population Data   E. Niclas Jonsson, Mats O. Karlsson and Peter A. Milligan

183

8

The Epistemology of Pharmacometrics   Paul J. Williams, Yong Ho Kim and Ene I. Ette

223

9

Data Imputation   Ene I. Ette, Hui-May Chu and Alaa Ahmad

245

PART II

POPULATION PHARMACOKINETIC BASIS OF PHARMACOMETRICS

10

Population Pharmacokinetic Estimation Methods   Ene I. Ette, Paul J. Williams and Alaa Ahmad

265

11

Timing and Efficiency in Population Pharmacokinetic/Pharmacodynamic Data Analysis Projects   Siv Jönsson and E. Niclas Jonsson

287

12

Designing Population Pharmacokinetic Studies for Efficient Parameter Estimation   Ene I. Ette and Amit Roy

303

13

Population Models for Drug Absorption and Enterohepatic Recycling   Olivier Pétricoul, Valérie Cosson, Eliane Fuseau and Mathilde Marchand

345

14

Pharmacometric Knowledge Discovery from Clinical Trial Data Sets   Ene I. Ette

383

15

Resampling Techniques and their Application to Pharmacometrics   Paul J. Williams and Yong Ho Kim

401

16

Population Modeling Approach in Bioequivalence Assessment   Chuanpu Hu and Mark E. Sale

421

PART III

PHARMACOKINETICS/PHARMACODYNAMICS RELATIONSHIP: BIOMARKERS AND PHARMACOGENOMICS, PK/PD MODELS FOR CONTINUOUS DATA, AND PK/PD MODELS FOR OUTCOMES DATA

17

Biomarkers in Drug Development and Pharmacometric Modeling   Paul J. Williams and Ene I. Ette

457

18

Analysis of Gene Expression Data   Daniel Brazeau and Murali Ramanathan

473

19

Pharmacogenomics and Pharmacokinetic/Pharmacodynamic Modeling   Jin Y. Jin and William J. Jusko

509

20

Empirical Pharmacokinetic/Pharmacodynamic Models   James A. Uchizono and James R. Lane

529

21

Developing Models of Disease Progression   Diane R. Mould

547

22

Mechanistic Pharmacokinetic/Pharmacodynamic Models I   Varun Garg and Ariya Khunvichai

583

23

Mechanistic Pharmacokinetic/Pharmacodynamic Models II   Donald E. Mager and William J. Jusko

607

24

PK/PD Analysis of Binary (Logistic) Outcome Data   Jill Fiedler-Kelly

633

25

Population Pharmacokinetic/Pharmacodynamic Modeling of Ordered Categorical Longitudinal Data   Ene I. Ette, Amit Roy and Partha Nandy

655

26

Transition Models in Pharmacodynamics   Ene I. Ette

689

27

Mixed Effects Modeling Analysis of Count Data   Christopher J. Godfrey

699

28

Mixture Modeling with NONMEM V   Bill Frame

723

PART IV

CLINICAL TRIAL DESIGNS

29

Designs for First-Time-in-Human Studies in Nononcology Indications   Hui-May Chu, Jiuhong Zha, Amit Roy and Ene I. Ette

761

30

Designs of Phase 1 Studies in Oncology   Brigitte Tranchand, René Bruno and Gilles Freyer

781

31

Designs and Analysis of Clinical Exposure: Response Trials   David Hermann, Raymond Miller, Matthew Hutmacher, Wayne Ewy and Kenneth Kowalski

803

PART V

PHARMACOMETRIC KNOWLEDGE CREATION

32

Pharmacometric/Pharmacodynamic Knowledge Creation: Toward Characterizing an Unexplored Region of the Response Surface   Ene I. Ette and Hui-May Chu

829

33

Clinical Trial Simulation: Theory   Peter L. Bonate

851

34

Modeling and Simulation: Planning and Execution   Paul J. Williams and James R. Lane

873

35

Clinical Trial Simulation: Efficacy Trials   Mathew M. Riggs, Christopher J. Godfrey and Marc R. Gastanguay

881

PART VI

PHARMACOMETRIC SERVICE AND COMMUNICATION

36

Engineering Pharmacometrics Enterprise   Thaddeus H. Grasela and Charles W. Dement

903

37

Communicating Pharmacometric Analysis Outcome   Ene I. Ette and Leonard C. Onyiah

925

PART VII

SPECIFIC APPLICATION EXAMPLES

38

Pharmacometrics Applications in Population Exposure-Response for New Drug Development and Evaluation   He Sun and Emmanuel O. Fadiran

937

39

Pharmacometrics in Pharmacotherapy and Drug Development: Pediatric Application   Edmund V. Capparelli and Paul J. Williams

955

40

Pharmacometric Methods for Assessing Drug-Induced QT and QTc Prolongations for Non-Antiarrhythmic Drugs   He Sun

977

41

Using Pharmacometrics in the Development of Therapeutic Biological Agents   Diane R. Mould

993

42

Analysis of Quantic Pharmacokinetic Study: Robust Estimation of Tissue-to-Plasma Ratio   Hui-May Chu and Ene I. Ette

1035

43

Physiologically Based Pharmacokinetic Modeling: Inhalation, Ingestion, and Dermal Absorption   Sastry S. Isukapalli, Amit Roy and Panos G. Georgopoulos

1069

44

Modeling of Metabolite Pharmacokinetics in a Large Pharmacokinetic Data Set: An Application   Valérie Cosson, Karin Jorga and Eliane Fuseau

1107

45

Characterizing Nonlinear Pharmacokinetics: An Example Scenario for a Therapeutic Protein   Stuart Friedrich

1137

46

Development, Evaluation, and Applications of in Vitro/in Vivo Correlations: A Regulatory Perspective   Patrick J. Marroum

1157

47

The Confluence of Pharmacometric Knowledge Discovery and Creation in the Characterization of Drug Safety   Hui-May Chu and Ene I. Ette

1175

Index

1197