Isoniazid Mediates the CYP2B6*6 Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6

Abstract

Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the CYP2B6*6/*6 genotype (but not the CYP2B6*1/*1 genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time-and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using geno- allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.

Model‐Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co‐Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy

“…Efavirenz is mainly metabolized via CYP2B6 and CYP2A6, and slow metabolizers with regard to NAT2 and CYP2B6 have elevated plasma levels of efavirenz when TB drugs are concomitantly administered . INH has been shown to inhibit CYP2A6 resulting in increased exposure to efavirenz in CYP2B6 slow metabolizers . The results presented here suggest that efavirenz‐based ART increases ACINH and INA clearances resulting in lower exposure of the metabolites.…”

A proposed management algorithm for late-onset efavirenz neurotoxicity

“…Furthermore, limited studies of INHinduced cerebral toxicity document earlier onset of symptoms (mean 21 days). [11,13] We were unable to measure INH blood levels in our patients.…”

“…This has previously been noted in a pharmacodynamic study. [10,11] INH has also been independently associated with neuropsychiatric effects, occurring a median of 21 days after initiation of treatment. [12,13] We have noted a recent increase in cases of EFV toxicity presenting to our tertiary neurology referral unit in the Western Cape Province, SA, over a relatively short period of time.…”

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

“…Efavirenz Metabolism Using the HepatoPac In Vitro Model. A long-term incubation of a human hepatocyte model (HepatoPac) (Ramsden et al, 2015) was used to identify the contribution of CYP2A6, CYP2B6, CYP3A4, and uridine 59-diphosphoglucuronosyltransferase (UGT; predominately UGT2B7) toward efavirenz metabolism (di Iulio et al, 2009;Kwara et al, 2009;Ogburn et al, 2010;Court et al, 2014) (Table 4). Induced human HepatoPac (with 10 mM 14 C-efavirenz) plates were then further incubated with and without inducers for 72 hours (10 mM rifampin, 10 mM efavirenz, or 100 mM carbamazepine) or inhibitors (50 mM erythromycin, 10 mM ticlopidine, 10 mM telmisartan, or 10 mM PCPAH).…”