Pharmacokinetic interaction between efavirenz and rifampicin in healthy volunteers

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

“…Thus, it is possible that CYP2B6 is near maximally induced under efavirenz steady-state setting, diminishing the full intrinsic induction potential of rifampin on this enzyme. This suggestion is supported by the present data and results from another study where rifampin (450 mg/day) treatment for a week reduced AUC 0–∞ of a single 600 mg oral dose of efavirenz 600 by nearly 3-fold [39]. It follows that, for CYP2B6 substrates that autoinduce metabolism (e.g.…”

“…It follows that, for CYP2B6 substrates that autoinduce metabolism (e.g. efavirenz, artimisinin, cyclophosphamide, ifosfamide, and nevirapine) [3,4], drug interactions from a single dose study may not reliably predict steady-state drug interactions because they seem to over predict the magnitude of change as dearly shown by the quantitative difference between rifampin–efavirenz interactions at single (present data and [39]) and multiple efavirenz dosing studies, i.e., the impact of rifampin (and other inducers) on the steady state disposition of the autoinducer drug is likely to be small. This also appears to explain the lack of clinically significant effect of rifampin-based anti-TB on steady-state efavirenz exposure [29,30,41,42] and clinical outcomes [43–45] of efavirenz-based HIV therapy.…”

“…Rifampin is known to enhance CYP2B6 activity in primary human hepatocytes [24,25], and, consistent with these in vitro data, rifampin enhances the elimination of known CYP2B6 substrates in vivo (e.g., ketamine [27], bupropion [15] and methadone [26]). Although efavirenz metabolite data were not reported to gain mechanistic insight, rifampin has been shown to significantly reduce the exposure of a single 600 mg oral dose of efavirenz in a small study in healthy volunteers [39]. Taking the present data and literature evidence together, we conclude that: CYP2B6 plays a central role in efavirenz clearance in vivo ; the inclusion of full pharmacokinetic analysis of efavirenz metabolites for the first time provided plausible mechanism by which rifampin enhances efavirenz elimination, i.e., rifampin enhances efavirenz elimination through induction of CYP2B6-mediated efavirenz 8-hydroxylation; and a single dose of efavirenz may be a reliable biomarker in evaluating induction drug interactions mediated by CYP2B6.…”

Drug–Drug Interactions of Infectious Disease Treatments in Low‐Income Countries: A Neglected Topic?

“…Among the first‐line HIV medications, efavirenz is most susceptible to interactions because it is a substrate of CYP2B6, an enzyme that is not only polymorphic but also inducible by rifampin. When studied in healthy volunteers, repeated dosing of rifampin (450 mg/day for 7 days) significantly decreased the AUC of efavirenz (38.6%) . This result has also been observed in multiple other studies completed in healthy volunteers, with a significant decrease in efavirenz exposure by coadministration with rifampin (range: 17.8–61.0% decrease), and in all cases, the decreased exposure is attributed to induction of CYP2B6 by rifampin (half‐maximal effective concentration = 0.127 μM) .…”

Conference report: pharmacogenomics in special populations at WCP2018

“…A distinct population‐specific efavirenz–rifampicin drug interaction profile required varying efavirenz dose recommendations for TB‐HIV patients during rifampicin‐based anti‐TB cotreatment. Rifampicin, a potent inducer of efavirenz‐metabolizing enzymes (CYP2B6, CYP2A6 and CYP3A4), significantly reduces plasma efavirenz concentration in white individuals . Accordingly, the FDA and the British HIV Association recommend that the dose of efavirenz is increased (to 800 mg day –1 ) during rifampicin cotherapy .…”