Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Abstract

Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirineatorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.

Evaluation of the Pharmacokinetics of Metformin Following Coadministration With Doravirine in Healthy Volunteers

“…The results suggested no clinically relevant effects of doravirine on the PK of metformin and that dose adjustment of metformin is not required when coadministered with doravirine. The current data are consistent with previous in vitro studies 18 and clinical trials, 12,25,26,[31][32][33] which have suggested that doravirine is unlikely to be responsible for DDIs through its actions on metabolizing enzymes and transporters. Doravirine has been shown in in vitro/in vivo studies to be primarily metabolized via oxidative metabolism by CYP3A 17,18 and is also a substrate for P-glycoprotein (P-gp) in vitro 17 ; however, in vivo data suggest P-gp is unlikely to play a significant role in its absorption and elimination.…”

“…Doravirine has been shown in in vitro/in vivo studies to be primarily metabolized via oxidative metabolism by CYP3A 17,18 and is also a substrate for P-glycoprotein (P-gp) in vitro 17 ; however, in vivo data suggest P-gp is unlikely to play a significant role in its absorption and elimination. 17 Furthermore, in vitro and clinical data demonstrate that doravirine has low potential to modulate CYPs 12,18,25,26 or major drug transporters, including the organic anion transporting polypeptide (OATP) 1B1/B3, breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1/3, and organic cation transporter (OCT) 2. 18 Doravirine has been shown previously not to have a clinically meaningful effect on the PK of substrates of CYP3A, 12,25,26,[31][32][33] OATP1B1, 26,32 P-gp, 25,26,32 BCRP, 25,26,32 or uridine 5 -diphosphoglucuronosyltransferase 1A1/3/9.…”

Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone

“…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][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.…”