Reaction phenotyping to assess victim drug-drug interaction risks

ABSTRACT

Introduction: Reaction phenotyping provides critical information regarding the fraction metabolized (f_m) of drug candidates. It has become increasingly important in drug discovery and development as it can be used to assess victim drug-drug interaction potential, guide structural modification to reduce f_m, inform clinical study design, predict individual variability in pharmacokinetics, and evaluate the impact of genetic polymorphisms.

Areas covered: The currently available in vitro and in vivo methods for reaction phenotyping are summarized along with their advantages, limitations and timings for application during the different stages of drug discovery and development. Challenges of reaction phenotyping for low clearance compounds, non-Cytochrome P450 (CYP) enzymes, extrahepatic contribution and atypical kinetics are highlighted and various approaches are discussed.

Expert opinion: Certain areas of reaction phenotyping remain challenging with the current state of the science. In order to better define f_m in this challenging space, there needs to be future advances in selective inhibitors and specific substrate reactions for non-CYP enzymes, availability of high quality and low cost recombinant enzymes, tissue distribution and in vitro-in vivo correlation, scaling factors for extrahepatic enzymes and the next generation of low clearance tools.

KEYWORDS:

• Metabolism
• clearance
• fraction metabolized
• reaction phenotyping
• cytochrome P450
• UGT
• atypical enzyme kinetics
• low clearance
• inhibitors
• pharmacokinetics

Article highlights

• Reaction phenotyping provides useful information on victim DDI potential, individual PK variability and impact of genetic polymorphism.

• In vitro and in vivo methods are available for reaction phenotyping in drug discovery and development, including HLM or HHEP with chemical inhibitors or antibodies and human recombinant enzymes with RAF or ISEF.

• HHEP is a preferred system over HLM or recombinant enzymes as it is more physiologically relevant and has a complete complement of drug metabolizing enzymes and cofactors. HHEP with chemical inhibitors and monitoring parent depletion provides a non-bias approach to assess f_m and clearance pathways.

• Standard systems (e.g. recombinant enzymes, HLM, HHEP) are not suitable for reaction phenotyping of low clearance compounds based on parent depletion. Approaches for reaction phenotyping of low clearance compounds include the hepatocyte relay assay, measuring metabolite formation rate and using radio-labelled material.

• Reaction phenotyping of non-CYP or extrahepatic enzymes and enzyme-transporter interplay remains to be challenging. Future advancement in these areas of science and technology will help better define f_CL for these pathways in vivo with in vitro and modeling tools.

• The understanding of concentration dependence in f_CL can  help to more accurately predict the clinical DDI outcome for compounds which exhibit non-conventional kinetic profile.

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Acknowledgments

The author would like to thank Jian Lin, Xin Yang, Kimberly Lapham and Chang Cheng for helpful discussion; Sophia Shi and Karen Atkinson for editing the manuscript as well as Larry Tremaine and Tess Wilson for their leadership and support.

Declaration of interest

L Di is an employee of Pfizer Inc. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.