Preface.

List of Contributors.

Part I: Introduction.

1 The Role of Pharmacokinetics and Pharmacodynamics in the Development of Biotech Drugs (Bernd Meibohm).

1.1 Introduction.

1.2 Biotech Drugs and the Pharmaceutical Industry.

1.3 Pharmacokinetics and Pharmacodynamics in Drug Development.

1.4 PK and PK/PD Pitfalls for Biotech Drugs.

1.5 Regulatory Guidance.

1.6 Future.

1.7 References.

Part II: The Basics.

2 Pharmacokinetics of Peptides and Proteins (Lisa Tang and Bernd Meibohm).

2.1 Introduction.

2.2 Administration Pathways.

2.3 Administration Route and Immunogenicity.

2.4 Distribution.

2.5 Elimination.

2.6 Interspecies Scaling.

2.7 Conclusions.

2.8 References.

3 Pharmacokinetics of Monoclonal Antibodies (Katharina Kuester and Charlotte Kloft).

3.1 Introduction.

3.2 The Human Immune System.

3.3 Physiological Antibodies.

3.4 Therapeutic Antibodies.

3.5 Effector Functions and Modes of Action of Antibodies.

3.6 Prerequisites for mAb Therapy.

3.7 Issues in the Bioanalysis of Antibodies.

3.8 Catabolism of Antibodies.

3.9 Pharmacokinetic Characteristics of mAbs.

3.10 Pharmacokinetic Modeling of mAbs.

3.11 Pharmacodynamics of mAbs.

3.12 Conclusions.

3.13 References.

4 Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides (Rosie Z. Yu, Richard S. Geary, and Arthur A. Levin).

4.1 Introduction.

4.2 Pharmacokinetics.

4.3 Pharmacodynamics.

4.4 Summary.

4.5 References.

5 Pharmacokinetics of Viral and Non-Viral Gene Delivery Vectors (Martin Meyer, Gururaj Rao, Ke Ren, and Jeffrey Hughes).

5.1 General Overview of Gene Therapy.

5.2 Anatomical Considerations.

5.3 Naked DNA.

5.4 Non-Viral Vectors.

5.5 Viral Vectors.

5.6 Summary.

5.7 References.

Part III: Challenges and Opportunities.

6 Bioanalytical Methods Used for Pharmacokinetic Evaluations of Biotech Macromolecule Drugs: Issues, Assay Approaches, and Limitations (Jean W. Lee).

6.1 Introduction.

6.2 Bioanalytical Methods for Macromolecule Drug Analysis: Common Considerations.

6.3 The Bioanalytical Method Workhorses.

6.4 Case Studies.

6.5 Future Perspectives: Emerging Quantitative Methods.

6.6 Conclusions.

6.7 References.

7 Limitations of Noncompartmental Pharmacokinetic Analysis of Biotech Drugs (Arthur B. Straughn).

7.1 Introduction.

7.2 The Concept of Volume of Distribution.

7.3 Calculation of Vss.

7.4 Pitfalls in Calculating Vss.

7.5 Results and Discussion.

7.6 Conclusions.

7.7 References.

8 Bioequivalence of Biologics (Jeffrey S. Barrett).

8.1 Introduction.

8.2 Prevailing Opinion: Science, Economics, and Politics.

8.3 Biologics: Time Course of Immunogenicity.

8.4 Pharmaceutical Equivalence.

8.5 Bioequivalence: Metrics and Methods for Biologics?

8.6 Case Study: Low-Molecular-Weight Heparins.

8.7 Conclusions.

8.8 References.

9 Biopharmaceutical Challenges: Pulmonary Delivery of Proteins and Peptides (Kun Cheng and Ram I. Mahato).

9.1 Introduction.

9.2 Structure and Physiology of the Pulmonary System.

9.3 Barriers to Pulmonary Absorption of Peptides and Proteins.

9.4 Strategies for Pulmonary Delivery.

9.5 Experimental Models.

9.6 Pulmonary Delivery of Peptides and Proteins.

9.7 Limitations of Aerosol Delivery.

9.8 Summary.

9.9 References.

10 Biopharmaceutical Challenges: Delivery of Oligonucleotides (Lloyd G. Tillman and Gregory E. Hardee).

10.1 Introduction.

10.2 ASOs: The Physico-Chemical Properties.

10.3 Local Administration.

10.4 Systemic Delivery.

10.5 Conclusions.

10.6 References.

11 Custom-Tailored Pharmacokinetics and Pharmacodynamics via Chemical Modifications of Biotech Drugs (Francesco M. Veronese and Paolo Caliceti).

11.1 Introduction.

11.2 Polymers Used in Biotechnological Drug PEGylation.

11.3 Advantages of PEG as Drug Carrier.

11.4 Chemical Aspects Critical for the Pharmacokinetics of Drug Conjugates.

11.5 Insulin.

11.6 Interferons.

11.7 Avidin.

11.8 Non-Peptide Drug Conjugation.

11.9 Concluding Remarks.

11.10 References.

12 Exposure–Response Relationships for Therapeutic Biologic Products (Mohammad Tabrizi and Lorin K. Roskos).

12.1 Introduction.

12.2 Overview of Pharmacokinetics and Pharmacodynamics.

12.3 Hormones.

12.4 Cytokines.

12.5 Growth Factors.

12.6 Soluble Receptors.

12.7 Monoclonal Antibodies (mAbs).

12.8 Conclusions.

12.9 References.

Part IV: Examples for the Integration of Pharmacokinetic and Pharmacodynamic Concepts Into the Biotech Drug Development Plan.

13 Preclinical and Clinical Drug Development of Tasidotin, a Depsi-Pentapeptide Oncolytic Agent (Peter L. Bonate, Larry Arthaud, and Katherine Stephenson).

13.1 Introduction.

13.2 The Dolastatins.

13.3 Discovery and Preclinical Pharmacokinetics of Tasidotin.

13.4 Preclinical Pharmacology of Tasidotin and ILX651-C-Carboxylate.

13.5 Toxicology of Tasidotin.

13.6 Clinical Pharmacology and Studies of Tasidotin in Patients with Solid Tumors.

13.7 Clinical Pharmacology of ILX651-C-Carboxylate.

13.8 Exposure–Response Relationships.

13.9 Discussion.

13.10 Summary.

13.11 References.

14 Clinical Drug Development of Cetuximab, a Monoclonal Antibody (Arno Nolting, Floyd E. Fox, and Andreas Kovar).

14.1 Introduction.

14.2 Specific Considerations in Oncologic Drug Development.

14.3 Introduction to the Clinical Pharmacokinetics of Cetuximab.

14.4 Early Attempts to Characterize the PK of Cetuximab.

14.5 PK of Cetuximab Following Pooling of Data Across All Studies.

14.6 Characterization of Cetuximab PK by a Population PK Approach.

14.7 Drug–Drug Interaction Studies.

14.8 Conclusions.

14.9 References.

15 Integration of Pharmacokinetics and Pharmacodynamics Into the Drug Development of Pegfilgrastim, a Pegylated Protein (Bing-Bing Yang).

15.1 Introduction.

15.2 Overview of Filgrastim Pharmacokinetics.

15.3 The Making of Pegfilgrastim.

15.4 Preclinical Pharmacokinetics and Pharmacodynamics of Pegfilgrastim.

15.5 Pharmacokinetic and Pharmacodynamic Modeling.

15.6 Clinical Pharmacokinetics and Pharmacodynamics of Pegfilgrastim.

15.7 Basis for the Fixed-Dose Rationale.

15.8 Clinical Evaluation of the Fixed Dose.

15.9 Summary.

15.10 References.

Subject Index.