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

Abstract

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. AIMSTo catalogue the perpetrators of CYP-mediated pharmacokinetic drug-drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. METHODSCandidate 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 Նsix 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 (Նtwofold 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. RESULTSFrom 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. CONCLUSIONSUsing 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.

In Vivo Information-Guided Prediction Approach for Assessing the Risks of Drug-Drug Interactions Associated with Circulating Inhibitory Metabolites

“…According to the FDA classifications of strong, moderate, or weak inhibitors (FDA Draft Guidance for Industry, 2012), these perpetrators may be strong inhibitors of CYP2C9. However, no strong inhibitor of CYP2C9 was listed in the new FDA draft guidance and a recent criteriabased assessment of perpetrators (Polasek et al, 2011). Although these three perpetrators have limited clinical application, they may serve as useful tools for drug metabolism studies.…”

“…Furthermore, the CR of most CYP2C9 substrates cannot be calculated by eq. 4 because of the absence of IR data (e.g., The IR value can be assumed to be 1 for a very strong P450 inhibitor, but no strong inhibitor of CYP2C9 has been found according to the new FDA Draft Guidance for Industry and a recent study (Polasek et al, 2011). Therefore, the CR of CYP2C9 substrates was estimated using eq.…”

Drug interactions: principles and practice

“…Perpetrator drugs known to strongly affect drug metabolism (Table 2) are more likely to cause large concentration changes and hence clinical consequences. 4 Recognising these potential perpetrators of pharmacokinetic drug-drug interactions is important.…”

Letter by Bouatou et al Regarding Article, “Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation”

“…Then, the chosen list of CYP3A4/P-gp inhibitors is not exhaustive and their potency of CYP3A4/P-gp inhibition (moderate versus strong) is debated in the literature. 3 We have developed a table of clinically relevant CYP and P-gp substrates, inhibitors, and inducers with their potency of inhibition/induction to evaluate potential drug-drug interactions, which is updated yearly by clinical pharmacologists.2 As others, we do not consider azithromycin as a clinically relevant CYP3A4 inhibitor, 4 and several inhibitors are either missing or misclassified as moderate inhibitors.2,3 Also, in this retrospective analysis, 1 comedications have only been assessed at baseline. This is of limited relevance, because a potential drug-drug interaction perpetrator is not expected to have the same clinical impact, depending on dose, duration, and timing of comedication use.…”

“…Then, the chosen list of CYP3A4/P-gp inhibitors is not exhaustive and their potency of CYP3A4/P-gp inhibition (moderate versus strong) is debated in the literature. 3 We have developed a table of clinically relevant CYP and P-gp substrates, inhibitors, and inducers with their potency of inhibition/induction to evaluate potential drug-drug interactions, which is updated yearly by clinical pharmacologists.…”