Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study.

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 doravirine-atorvastatin/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.

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type-1 (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, type 2 diabetes mellitus is often treated with metformin. Perturbations of metformin absorption or elimination may affect its safety and efficacy profile; therefore, understanding potential drug-drug interactions between doravirine and metformin is important. An open-label, fixed-sequence, 2-period trial in healthy adults was conducted. Single-dose metformin 1000 mg was administered in period 1; in period 2, doravirine 100 mg was administered once daily on days 1 to 7, and single-dose metformin 1000 mg was administered on day 5. Plasma pharmacokinetics for metformin alone and coadministered with doravirine were assessed. Fourteen participants enrolled and completed the trial. Least-squares geometric mean ratios and 90% confidence intervals of metformin AUC0-∞ , and Cmax following coadministration of metformin and doravirine compared with metformin alone were 0.94 (0.88-1.00) and 0.94 (0.86-1.03), respectively; metformin Tmax and half-life were also minimally impacted. These data indicate that doravirine did not have a clinically relevant effect on the pharmacokinetics of metformin. Metformin alone and coadministered with doravirine was generally well tolerated. These data support coadministration of doravirine 100 mg and metformin 1000 mg without dose adjustment.

A Study to Evaluate Doravirine Pharmacokinetics When Coadministered With Acid-Reducing Agents.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus type 1 infection. Because of potential concomitant administration with acid-reducing agents, a drug-interaction trial was conducted to evaluate the potential impact of these types of medications on doravirine pharmacokinetics. In an open-label, 3-period, fixed-sequence trial, healthy adult participants received the following: period 1, a single dose of doravirine 100 mg; period 2, coadministration of a single dose of doravirine 100 mg and an antacid (1600 mg aluminum hydroxide, 1600 mg magnesium hydroxide, and 160 mg simethicone); period 3, 40 mg pantoprazole once daily on days 1-5 coadministered with a single dose of doravirine 100 mg on day 5. There was a minimum 10-day washout between periods. Plasma samples for pharmacokinetic evaluation were collected, and safety was assessed. Fourteen participants (8 male, 6 female) were enrolled, and 13 completed the trial. Geometric mean ratios (90% confidence intervals) for doravirine AUC0-inf , Cmax , and C24 for doravirine + antacid/doravirine were 1.01 (0.92-1.11), 0.86 (0.74-1.01), and 1.03 (0.94-1.12), respectively, and for doravirine + pantoprazole/doravirine were 0.83 (0.76-0.91), 0.88 (0.76-1.01), and 0.84 (0.77-0.92), respectively. Doravirine was generally well tolerated administered alone or with either of the acid-reducing agents. Coadministration of an aluminum/magnesium-containing antacid or pantoprazole did not have a clinically meaningful effect on doravirine pharmacokinetics, supporting the use of acid-reducing agents with doravirine.

Multiple Doses of Rifabutin Reduce Exposure of Doravirine in Healthy Subjects.

Doravirine is a nonnucleoside reverse transcriptase inhibitor in clinical development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretroviral therapies. The cytochrome P450 (CYP)3A-dependent metabolism of doravirine makes it susceptible to interactions with modulators of this pathway, including the antituberculosis treatment rifampin. Rifabutin, an alternative antibiotic used to treat tuberculosis, may have a lower-magnitude effect on CYP3A. The aim of this trial was to determine the effect of steady-state rifabutin on doravirine single-dose pharmacokinetics and tolerability. In this open-label, 2-period, fixed-sequence, drug-drug interaction study, healthy subjects received a single dose of doravirine 100 mg alone and coadministered on day 14 of once-daily administration of rifabutin 300 mg for 16 days. Plasma samples were taken to determine doravirine pharmacokinetics, and safety was monitored throughout. Dose adjustment of doravirine in the presence of coadministered rifabutin was explored through nonparametric superposition analysis. Rifabutin reduced doravirine area under the concentration-time curve from time zero to infinite and plasma drug concentration 24 hours postdose with geometric mean ratios ([rifabutin+doravirine]/[doravirine alone]) (90%CIs) of 0.50 (0.45-0.55) and 0.32 (0.28-0.35), respectively. Doravirine apparent clearance increased from 5.9 L/h without rifabutin to 12.2 L/h when coadministered. Doravirine pharmacokinetics with and without coadministered rifabutin were not equivalent. Nonparametric superposition analysis projected that administration of doravirine 100 mg twice daily with rifabutin will restore steady-state trough concentration values to efficacious levels associated with doravirine 100 mg once daily in the absence of CYP3A inducers. Doravirine may be coadministered with rifabutin when the doravirine dose frequency is increased from 100 mg once daily to 100 mg twice daily.