Evaluation of CYP2B6 Induction and Prediction of Clinical Drug-Drug Interactions: Considerations from the IQ Consortium Induction Working Group--An Industry Perspective

Abstract

Drug-drug interactions (DDIs) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. This work aimed to evaluate the potency of CYP2B6 versus CYP3A4 induction in vitro and from clinical studies and to assess the predictability of efavirenz versus bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo. The magnitude of DDIs caused by induction could not be predicted for bupropion with static or dynamic models. On the other hand, the relative induction score, net effect, and physiologically based pharmacokinetics SimCYP models using efavirenz resulted in improved DDI predictions. Although bupropion and efavirenz have been used and are recommended by regulatory agencies as clinical CYP2B6 probe substrates for DDI studies, CYP3A4 contributes to the metabolism of both probes and is induced by all reference CYP2B6 inducers. Therefore, caution must be taken when interpreting clinical induction results because of the lack of selectivity of these probes. Although in vitro-in vivo extrapolation for efavirenz performed better than bupropion, interpretation of the clinical change in exposure is confounded by the coinduction of CYP2B6 and CYP3A4, as well as the increased contribution of CYP3A4 to efavirenz metabolism under induced conditions. Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 (fraction metabolized > 0.9) is needed to improve in vitro-in vivo extrapolation for characterizing the potential for CYP2B6-mediated DDIs. Alternative strategies and a framework for evaluating the CYP2B6 induction risk are proposed.

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

“…Questions continue regarding the best in vivo CYP2B6 probe. Racemic bupropion, and more specifically racemic bupropion hydroxylation, is the standard in vivo probe for CYP2B6 activity, polymorphisms, and drug interactions, and is recommended by regulatory agencies . Bupropion clearance and plasma AUC do not reflect CYP2B6 activity because hydroxylation is a minor route of elimination.…”

“…One of the greater unknowns is the reason why plasma R,R‐ and S,S‐hydroxybupropion concentrations are so different . Alternative CYP2B6 probes have also been suggested, such as 8‐hydroxylation of efavirenz, whose metabolism in vitro was considered to be a better predictor of clinical drug interactions than bupropion …”

“…Racemic bupropion, and more specifically racemic bupropion hydroxylation, is the standard in vivo probe for CYP2B6 activity, polymorphisms, and drug interactions, and is recommended by regulatory agencies. 19,20 Bupropion clearance and plasma AUC do not reflect CYP2B6 activity because hydroxylation is a minor route of elimination. More commonly used is the plasma hydroxybupropion/bupropion AUC ratio, but this is confounded because racemic hydroxybupropion is Figure 1 were also genotyped for the POR*5, *8, and *28 alleles, as well as the g.6593 A>G polymorphism.…”

“…Clinically, racemic bupropion hydroxylation has been used to phenotype CYP2B6 activity, polymorphisms, and drug interactions, and is the recommended standard in vivo CYP2B6 probe. 19,20 The CYP2B6 gene is highly polymorphic, and carriers of allelic variants have altered in vivo bupropion metabolism, evidenced by the plasma hydroxybupropion/ bupropion area under the curve (AUC) ratio, although bupropion clearance is unchanged. 16,[21][22][23][24][25] Hydroxybupropion may also inhibit P450 to a similar or greater extent than the parent drug.…”

“…In vitro it is catalyzed predominantly by CYP2B6, and is the standard in vitro probe for assessing CYP2B6 activity and drug interactions. Clinically, racemic bupropion hydroxylation has been used to phenotype CYP2B6 activity, polymorphisms, and drug interactions, and is the recommended standard in vivo CYP2B6 probe . The CYP2B6 gene is highly polymorphic, and carriers of allelic variants have altered in vivo bupropion metabolism, evidenced by the plasma hydroxybupropion/bupropion area under the curve (AUC) ratio, although bupropion clearance is unchanged .…”