Etravirine: Clinical Pharmacology

Hopkins HIV Report 2006 Sep; 18(5):15

Adriana Andrade, M.D.
Johns Hopkins

The most relevant clinical pharmacology presentations during the XVI International AIDS Conference pertained to etravirine (ETV, TMC125), the second-generation investigational NNRTI from Tibotec that will soon be available through an expanded access program. ETV is a cytochrome P450 (CYP450) enzyme CYP3A4 substrate and also an inhibitor and inducer of several other CYP isoforms, making it susceptible to pharmacokinetic interactions with drugs metabolized through this pathway. Discussed below are data presented on drug interactions of etravirine with opioid replacement therapy and with acid-reducing agents.

Etravirine and Methadone

Substance abuse is prevalent in the HIV-infected population. Methadone, a µ-opioid receptor agonist used for the treatment of opioid addiction, is a substrate of CYP3A4, 2B6, and 2C19. Pharmacokinetic interactions with methadone have been established for a number of antiretroviral drugs, including the induction of its metabolism by the NNRTIs efavirenz and nevirapine. Thus, questions about the safety of coadministering methadone and HAART surface frequently in clinical practice. ETV inhibits CYP3A4 and 2D6 and induces 2C8, 2C9, 2C18, and 2C19 in vitro and thus could potentially alter methadone plasma concentrations and lead to narcotic overdose or withdrawal.

Scholler-Gyure and her colleagues from Tibotec evaluated the two-way interaction between methadone and ETV in an open-label, steady-state pharmacokinetic study [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. TUPE0084]. Methadone is a chiral mixture of the inactive S-(+) and active R-(-) enantiomers; all opioid activity resides in the active R-(-) form. Sixteen HIV-negative males on individualized methadone maintenance therapy (dose range, 60-130 mg/day) were treated with ETV 100 mg bid for 14 days. The mean methadone AUC_12h, C_max and C_min decreased by 7%, 6%, and 9%, respectively, on day 7 for S-(+) methadone, and increased by 8%, 12% and 3%, respectively, for R-(-) methadone. The mean methadone AUC_12h, C_max and C_min all decreased by 11% on day 14 for methadone S-(+), and they increased by +6%, +10% and +2%, respectively, for methadone R-(-), when coadministered with ETV compared to when given alone. These changes were not considered to be clinically significant and were not associated with opiate withdrawal symptoms requiring modification of the methadone dose. ETV plasma concentrations were not affected by methadone coadministration.

These results suggest that the combination of methadone and ETV does not result in harmful pharmacokinetic drug interactions. It remains to be determined whether the lack of pharmacokinetic interaction with ETV will hold true for other opioid replacement agents such as buprenorphine, which is also a substrate of the CYP3A4 enzyme.

Etravirine and Acid-Reducing Agents

Gastroesophageal reflux disease is a prevalent condition in patients with HIV infection and requires treatment with acid-lowering agents. For some antiretroviral agents, absorption is highly dependent on optimal acidic gastric pH. Thus, coadministration of antiretrovirals and acidlowering agents could potentially interfere with antiretroviral absorption and lead to subtherapeutic levels and treatment failure.

The same group of investigators from Tibotec investigated the effects of the proton pump inhibitor omeprazole and the H2 blocker ranitidine on plasma concentrations of ETV [Scholler-Gyure M, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. TUPE0082]. In this open-label, three-period, cross-over pharmacokinetic study, 19 HIV-negative healthy volunteers (7 females/12 males) were evaluated: In period 1 subjects received a single dose of ETV 100 mg; in period 2 they were given ranitidine 150 mg po bid for 11 days + a single dose of ETV 100 mg on day 8; in period 3 they were given omeprazole 40 mg po qd for 11 days + a single dose of ETV 100 mg on day 8. Treatment periods were separated by 14 days. The ETV steady-state mean C_max and the AUC_last decreased by 3% and 16%, respectively, in the presence of ranitidine and increased by 13% and 41%, respectively, when coadministered with omeprazole. The reduction in ETV plasma concentrations when coadministered with ranitidine was not considered clinically significant. The increase in ETV plasma concentrations probably reflects inhibition of CYP2C19 by omeprazole and is not thought to have clinical relevance given the safety profile of ETV. There were no serious adverse events or discontinuations, and the study drugs were well tolerated.

In summary, ETV can be safely coadministered with methadone, ranitidine or omeprazole. This is fortunate, since these drugs are commonly used in the treatment of patients with HIV disease.

2006-09-10
HHR-2006-09-06

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