In Vitro Evaluation of the Drug Interaction Potential of Doravirine

Abstract

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ϳ20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (Յ20%) were reported at doravirine concentrations of Ն10 M but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drugmetabolizing enzymes and transporters.

Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone

“…22 Indeed, in this study, no stereospecific interactions between doravirine and methadone were observed, as R-, S-, and total methadone PK were not affected by coadministration of doravirine, and similar values for AUC 0-24 , C max , and C 24 were observed in both the presence and absence of doravirine. As doravirine may be administered to people living with HIV on methadone maintenance therapy, a trial was conducted to assess a potential PK interaction.…”

“…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.…”

“…13 Doravirine is a novel nonnucleoside reverse transcriptase inhibitor designed to overcome the limitations of other drugs within the same class. 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. [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. 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.…”