Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing inter-individual variability in exposure

ABSTRACT

Introduction: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure.

Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization.

Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies. If precision KI dosing can facilitate a fraction of the reported observational benefits, then substantial gains in patient outcomes will be derived in a cost-effective manner.

KEYWORDS:

• Cytochromes P450
• inter-individual variability
• optimised dosing
• P-glycoprotein
• pharmacogenetics
• pharmacokinetics
• precision medicine
• small molecule kinase inhibitor
• therapeutic drug monitoring
• toxicity guided dosing

Article highlights

• Overview of KI molecular targets and mechanisms, indications and regulatory approvals

• Comprehensive summary of KI physiochemical and pharmacokinetic properties

• Description of major sources of inter-individual variability in KI pharmacokinetics focussing on common pathways involved in determining KI exposure

• Description of alternative approaches proposed for optimised KI dosing with appraisal of current supporting evidence

• Analysis of challenges and knowledge gaps for KI dose optimisation approaches

This box summarizes key points contained in the article.

Acknowledgments

In addition to the listed authors, we gratefully acknowledge the additional insights of Bill J. Smith.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.