Importance of multi-p450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data

Abstract

Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is coadministered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contribute half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database. A total of 38 multi-P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450s, were identified. Seventeen (45%) multi-P450 inhibitors were strong inhibitors of at least one P450, and an additional 12 (32%) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam, while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine, and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate studies with the same inhibitors. The results of this study suggest that inhibition of multiple clearance pathways in vivo is clinically relevant, and the risk of DDIs with object drugs may be best evaluated in studies using multi-P450 inhibitors.

Figure 1

Simulation of the effect of minor pathway inhibition on AUC ratio for a probe drug with an f_m,1 of 0.87 and f_m,2 of 0.13. The probe drug was assumed to have an F_g of 0.8 due to metabolism by enzyme 2. Panel A focuses on the situation where the inhibition of the minor elimination pathway and F_g is predominant and a weak inhibition of enzyme 1 is observed. The magnitude of AUC change is shown as a function of 1+[I]/Ki for enzyme 2. Panel B focuses on the situation where the main enzyme inhibited is the major elimination pathway (enzyme 1) and weaker or equal inhibition of enzyme 2 and F_g (mediated by enzyme 2) is observed. Panel C shows a 3-dimentional depiction of the relationship between the in vivo AUC change, potency of the inhibitor towards enzyme 2 and the relative potency of the inhibitor towards enzyme 1 and enzyme 2.

Figure 2

Simulation of the effect of a multi-P450 inhibitor in comparison to selective inhibitors on the magnitude of the DDI. An object drug with three equally important clearance pathways with f_m = 0.32 and a renal clearance contributing to an f_e = 0.04 was considered. For this simulation, K_i,1 = K_i,2 = 10*K_i,3 and F_g = 0.66. Only enzyme 2 is present in the gut. The simulated AUC ratio is shown at increasing 1+I/K_i for enzyme 1.