Multiple Doses of Rifabutin Reduce Exposure of Doravirine in Healthy Subjects

Abstract

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.

Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone

“…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.…”

“…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.…”

Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics

“…Doravirine displays a 95% effective concentration of 20, 43, 27, and 55 nM against the WT, K103N, Y181C, and K103N/Y181C mutant viruses, respectively, in the presence of 50% human serum. 7 Doravirine is not highly bound to plasma protein (ß75%), and in vitro studies 8 as well as clinical drug-drug interaction trials conducted with modulators of CYP3A metabolism [9][10][11] suggest that CYP3A plays a major role in the metabolism of doravirine; less than 10% of doravirine is eliminated via renal excretion. 12 In a double-blind study involving healthy subjects, doravirine was demonstrated to be generally well tolerated over the dose range of 6-1200 mg. 4 The pharmacokinetic (PK) profile of these doses was investigated in the same study, and doravirine was demonstrated to achieve maximum plasma concentration (C max ) after 1-5 hours with an apparent terminal half-life (t 1/2 ) of 12-21 hours.…”

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

“…17 In vitro studies and clinical drug interaction studies indicated that cytochrome P450 (CYP)3A-mediated metabolism plays a major role in the elimination of doravirine. [17][18][19][20][21] Consistent with this, following oral administration of [ 14 C]-labeled doravirine to healthy subjects, the majority of the absorbed dose was recovered as oxidative metabolites, with minor amounts of conjugation products observed in excreta or in plasma. The major metabolite of doravirine observed in vitro in preparations from human liver and in excreta and plasma from humans was an oxidative metabolite.…”

“…20 Similarly, multiple dosing of the CYP3Ainducer rifabutin resulted in clinically meaningful reductions in doravirine exposure, requiring twice-daily administration of doravirine to compensate. 21 The clinical PK of doravirine and potential DDIs after the coadministration of commonly prescribed drugs has been previously reviewed. 27 As metformin is a commonly prescribed medication in individuals infected with HIV-1 who have type 2 diabetes mellitus, doravirine and metformin may be coadministered to treat both conditions.…”