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Pharmacokinetics and Pharmacodynamics of Tyrosine Kinase Inhibitors

  • Ana Ruiz-GarciaEmail author
  • Shinji Yamazaki
Chapter

Abstract

The importance of modeling and simulation approach is well recognized and established in the pharmaceutical industry. Establishing exposure-response relationships for new molecular entities’s efficacy and toxicity using a modeling and simulation approach has been shown to be critical in many aspects of regulatory decision making, including labeling. Among modeling and simulation approaches, pharmacokinetic-pharmacodynamic (PKPD) modeling is a powerful approach linking drug exposures to biological and pharmacological responses, providing a quantitative assessment of in vivo drug potency with mechanistic insight on drug action.

Protein tyrosine kinases (PTKs) play a key role in the regulation of a variety of transduction pathways. This protein family has proved to have a key role in cancer cells which has resulted in the design of highly selective tyrosine kinase inhibitors (TKIs) in oncology. This chapter presents a comprehensive overview of the PKPD work done for TKIs with preclinical data as well as the analyses performed in the clinical setting.

For the pre-clinical PKPD models, an appropriate PKPD model is generally selected based upon the underlying pharmacological mechanisms. This chapter will present examples of preclinical models for relationships between drug exposure and biomarker responses and relationships between drug exposure and antitumor effect. The PKPD modeling of clinical efficacy endpoints presented in this chapter included event free survival, cytogenetic and molecular responses, time to tumor progression, overall survival, objective response rate, tumor size changes and biomarker changes over time. The PKPD modeling of safety endpoints summarizes analyses preformed for fatigue, neutropenia, blood pressure changes, diarrhea, rash, and QT prolongation.

Keywords

Tyrosine kinase Pharmacokinetics Pharmacodynamics PKPD TKI modelling and simulation 

Notes

Acknowledgement

The authors would like to thank Paolo Vicini (Pharmacokinetics, Dynamics and Metabolism, Pfizer, San Diego, CA) for his critical insights and helpful discussions throughout the development of this chapter.

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Clinical Pharmacology, Global Research and Development, PfizerSan DiegoUSA
  2. 2.Pharmacokinetics Drug Metabolism, WW Research and Development, PfizerSan DiegoUSA

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