Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions

Abstract

Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K.

Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone

“…25 In vitro studies and clinical drug interaction studies indicated that CYP3A-mediated metabolism is a major contributor to the elimination of doravirine. 20,22,[26][27][28] Consistent with this finding, the majority of an absorbed oral dose of [ 14 C]-labeled doravirine in healthy subjects was recovered as oxidative metabolites. The oxidative metabolite M9 was the major metabolite of doravirine observed both in vitro in preparations from human liver and in vivo in human excreta and plasma.…”

“…These results are consistent with previous clinical trials in which doravirine has not been shown to be a perpetrator of DDIs as a concomitant partner with other medications. [18][19][20][21] The trial was conducted with methadone administered at steady state and doravirine administered for 5 days. The 5-day duration was selected because, based on the half-life of doravirine, steady-state concentrations were expected to be attained within 5 days.…”

“…10 In one study, the half-life of the R-and S-forms of methadone was reported to be 37.5 and 28.6 hours, respectively. 14,15 To date, preclinical and clinical data suggest that doravirine has minimal drug-drug interactions (DDIs) [18][19][20][21][22] as doravirine is not expected to either induce or inhibit any of the major CYP enzymes or transporters. 14,15 Phase 2 and 3 trials in treatment-naïve HIV-1-infected adults have shown that doravirine in combination with other antiretroviral agents is noninferior in terms of efficacy, but also demonstrates a more favorable safety profile compared with other treatment regimens.…”

“…14,15 To date, preclinical and clinical data suggest that doravirine has minimal drug-drug interactions (DDIs) [18][19][20][21][22] as doravirine is not expected to either induce or inhibit any of the major CYP enzymes or transporters. 20,22,[26][27][28] Consistent with this finding, the majority of an absorbed oral dose of [ 14 C]-labeled doravirine in healthy subjects was recovered as oxidative metabolites. 24 Low clearance (3.73 L/hr) and a moderate volume of distribution (60.5 L) were observed following intravenous administration of doravirine.…”

“…[14][15][16][17] In the United States, doravirine is indicated for administration once daily at a dose of 100 mg, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. 14,15 To date, preclinical and clinical data suggest that doravirine has minimal drug-drug interactions (DDIs) [18][19][20][21][22] as doravirine is not expected to either induce or inhibit any of the major CYP enzymes or transporters. 22,23 The rapid absorption of doravirine has been shown to result in a median time to maximum concentration (t max ) of 1 to 4 hours and a half-life of 12 to 19 hours for single oral doses of 6 to 1200 mg, 23 and a geometric mean maximum plasma concentration (C max ) of 2.26 μM was achieved at steady state following once-daily dosing.…”