Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Many drugs inhibit or induce cytochrome P450 enzymes (CYP) to cause clinically significant changes in the concentrations of other drugs, i.e. ‘perpetrate’ pharmacokinetic drug–drug interactions (PK‐DDIs). • Tables that list the substrates, inhibitors and inducers of CYP are common, but they lack consistency and are constructed from evidence of variable quality. WHAT THIS STUDY ADDS • This is the first study to catalogue important perpetrators of PK‐DDIs using objective criteria and clinical pharmacokinetic drug interaction studies. This information is intended to inform clinical decisions on PK‐DDIs. • Existing tables of CYP inhibitors and inducers have low sensitivity and low positive predictive value in identifying the major perpetrators of PK‐DDIs. • Several drugs were identified which potentially perpetrate CYP‐mediated PK‐DDIs, but quality clinical pharmacokinetic interaction studies are lacking. This information may be used to inform future research. AIMS To catalogue the perpetrators of CYP‐mediated pharmacokinetic drug–drug interactions (PK‐DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. METHODS Candidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (‘perpetrators’) were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of ≥six human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong , moderate or weak , whereas inducers were classified as major (≥twofold decrease in AUC) or weak (<twofold decrease in AUC). A catalogue of major perpetrators was constructed based on twofold changes in the clearance of probe substrates. Perpetrators in the clinical version of the Cytochromes P450 Drug Interaction Table (CDIT) were compared with the ‘accepted’ major perpetrators. RESULTS From a list of 216 candidate drugs (349 CYP‐perpetrator pairs, CYP‐PPs), 36 inhibitors and eight inducers were accepted as major perpetrators of PK‐DDIs, resulting in 58 CYP‐PPs. In comparison, the clinical version of the CDIT had a sensitivity of 33% and a positive predictive value of 68%. One hundred and ninety‐nine CYP‐PPs were rejected as major perpetrators, and 92 CYP‐PPs had insufficient published human pharmacokinetic data for robust classification. CONCLUSIONS Using a criteria‐based assessment, the number of drugs that are proven or likely major perpetrators of CYP‐mediated PK‐DDIs is relatively small. Current clinical decision support on PK‐DDIs is inconsistent with the published evidence and can be improved using simple criteria.