CYP3A activity: towards dose adaptation to the individual

ABSTRACT

Introduction: Co-medication, gene polymorphisms and co-morbidity are main causes for high variability in expression and function of the CYP3A isoenzymes. Pharmacokinetic variability is a major source of interindividual variability of drug effect and response of CYP3A substrates. While CYP3A genotyping is of limited use, direct testing of enzyme function (‘phenotyping’) may be more promising to achieve individualized dosing of CYP3A substrates.

Areas covered: We will discuss available phenotyping strategies for CYP3A isoenzymes and causes of intra- and interindividual variability of CYP3A. The impact of phenotyping on the dose selection and pharmacokinetics of CYP3A substrates (docetaxel, irinotecan, tyrosine kinase inhibitors, ciclosporin, tacrolimus) are reviewed. Pubmed searches were conducted during March–November 2015 to retrieve articles related to CYP3A enzyme, phenotyping, drug interactions with CYP3A probe substrates, and phenotyping-guided dosing algorithms.

Expert opinion: While ample data is available on the choice appropriate phenotyping drugs (midazolam, alfentanil, aplrazolam, buspirone, triazolam), less clinical trial data is available concerning strategies to usefully guide dosing in the clinical practice. Implementation into the clinical routine necessitates further research to identify (1) an easy-to-use and cheap test for CYP3A activity that (2) adequately predicts drug exposure to (3) allow a sound decision on dose adaptation and hence (4) improve clinical outcome and/or reduce the intensity or frequency of adverse drug effects.

KEYWORDS:

• Dosing strategies
• microdosing
• pharmacokinetics
• phenotyping
• TDM

Article highlights

• CYP3A isozymes are involved in the elimination of about 50% of the marketed drugs. Considerable intraindividual variability in activity of the intestinal and hepatic cytochrome P450 (CYP) 3A isozymes is expected in patient populations.

• Alfentanil, alprazolam, buspirone, midazolam, and triazolam are probe drugs for CYP3A that allow the quantification of CYP3A activity. Most data is available for midazolam.

• The ability to quantify an individual’s CYP3A-dependent elimination capacity and to dose accordingly can help to reduce PK variability and, hence, variability in drug response of CYP3A substrates with a narrow therapeutic index.

• PK of CYP3A substrates with a narrow therapeutic index, mainly anticancer agents and tests for CYP3A activity correlate and can be used to estimate the dose needed.

• Data concerning a clinical advantage in outcome and rate or intensity of adverse drug effects of such phenotyping-based dosing strategies are scarce and clinical trials should be encouraged.

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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.

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