Interpretation of Cytochrome P‐450 Inhibition and Induction Effects From Clinical Data: Current Standards and Recommendations for Implementation

Abstract

Agents that modify cytochrome P‐450 (CYP) enzyme activity are characterized as strong, moderate, or weak inhibitors or inducers based on the magnitude of their impact on substrate exposure in clinical studies. Criteria for these classifications are simple and semiquantitative. However, assignment of a given agent to a CYP inhibitor or inducer category is often complicated by limitations of the published data, inconsistent study findings, and other factors. CYP inhibitor and inducer categories are commonly used as a basis for differentiating drug interaction management recommendations. For example, product labeling for a CYP substrate may recommend avoidance in combination with strong inhibitors and dose reduction in combination with moderate inhibitors. When such recommendations exist, ambiguity or variability in placement of inhibitors or inducers into categories can introduce potentially harmful variations in clinical drug interaction management. Failure to adequately reflect the drug interaction potential of an agent by under‐categorizing it (e.g., calling it weak when data point to moderate effects), for example, may lead clinicians to respond inadequately to real risks, or to ignore potential interactions altogether. Over‐categorization may lead to actions such as over‐adjustment of substrate doses or unnecessary avoidance of optimal treatments. This review describes the current criteria for assignment of CYP inhibitor and inducer categories, summarizes common circumstances leading to ambiguous or variable CYP inhibitor and inducer categorizations, and proposes an approach to data interpretation and application of current criteria under uncertainty. When applied to > 1,000 CYP reviews, the approach described has identified a clear categorization in almost all cases.

How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial

“…The classification of inhibitors into strong, moderate, or weak classifications based on increases in substrate AUC, put forth by the FDA, is well accepted. However, results can vary from study to study, and several limitations exist that can impact the magnitude of the pharmacokinetic interaction, including but not limited to multiple pathways of metabolism, genetic variation, dose of inhibitor, or substrate given 12,39 . As Stout et al .…”

“…However, results can vary from study to study, and several limitations exist that can impact the magnitude of the pharmacokinetic interaction, including but not limited to multiple pathways of metabolism, genetic variation, dose of inhibitor, or substrate given. 12,39 As Stout et al points out, overcategorization of inhibitors may lead to potentially harmful actions. As such, it is important to integrate a reputable resource when considering CYP2D6 inhibitors in clinical practice.…”

Precision Dosing: The Clinical Pharmacology of Goldilocks

“…There is a need here for better standards for which drugs are strong, moderate, or weak inducers or inhibitors to ensure consistent clinical interpretation, appropriate categorization of each inhibitor and inducer, and proper dosing. In this issue of CPT, two papers provide important contributions to meet this need 1,2 . The work done by Yang et al 2 .…”

Possible inhibitory effects of terbinafine on aripiprazole metabolism: Two case reports

“…Terbinafine is an antifungal agent used for onychomycosis and a cytochrome P450 (CYP)2D6 inhibitor, which can increase the dextromethorphan/dextrorphan ratio 97-fold after 14 days of administration. 1,2 Several reports show that the CYP2D6 inhibiting effects of terbinafine occur within the first 4 days to 3 weeks of administration, [2][3][4] and this degree of inhibition is considered ''moderate'' 5 due to a 2-fold but ,5-fold increase in area under the concentration-time curve of the CYP2D6 substrate (ie, victim drug). [2][3][4] The duration of time during which the victim drug is moderately inhibited is at least 3 weeks following discontinuation of terbinafine.…”