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

Abstract

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 AUC 0-Ý , and C max 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 T max 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.Keywords antiretroviral therapy, doravirine, drug interaction, human immunodeficiency virus (HIV), metformin, type 2 diabetes, nonnucleoside reverse transcriptase inhibitor (NNRTI), pharmacokinetics

Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

“…Metformin is excreted unchanged in urine [ 80 ] and therefore not dependent on CYP3A-mediated metabolism. The lack of interaction of doravirine with metformin demonstrates that it has no clinically meaningful effect on the transporters involved in uptake and transport of metformin in vivo [ 29 ]—namely PMAT, OCT1, OCT2, OCT3, MATE1, and MATE2 K [ 80 , 81 ]—and confirms in vitro findings that doravirine has low potential for interactions with OCT2 and MATE1/2K [ 45 ].…”

“…Steady-state AUC was selected as the exposure measure from which to judge clinical relevance from a safety perspective, as this parameter is an integration of concentrations over the 24-h dosing interval in which individuals are exposed to doravirine at steady state. In phase I trials, there was no evidence that the incidence of overall AEs or specific AEs was temporally associated with doravirine T max [11,15,[20][21][22][23][24][25][26][27][28][29][30][31], therefore suggesting that C max does not play a major role in safety or tolerability. In the phase IIb trial, there was no evidence of exposure-or dose-related toxicities across the range of 25-200 mg doses evaluated, and no meaningful association between doravirine steady-state exposure and the incidence of neuropsychiatric AEs or fasting lipid levels that would further limit the exposure of doravirine from a safety perspective [17].…”

“…Doravirine was shown to have limited potential for clinically meaningful DDIs based on data obtained from in vitro studies of drug-metabolizing enzymes and drug transporters [10,45] and clinical studies [15,20,21,[26][27][28][29][30][31]. Since doravirine is a substrate of CYP3A4 [10], the most likely route of its involvement in DDIs is via inhibition and induction of CYP3A activity by strong and moderate CYP3A inhibitors/inducers.…”

“…Co-administration of doravirine and metformin had no clinically meaningful effect on metformin pharmacokinetics (Table 3 , Fig. 4 ) [ 29 ]. Metformin is excreted unchanged in urine [ 80 ] and therefore not dependent on CYP3A-mediated metabolism.…”

Pharmacokinetics, safety and tolerability of long‐acting parenteral intramuscular injection formulations of doravirine

“…At the therapeutic dose of 100 mg, orally administered doravirine is rapidly absorbed; the time to maximum concentration (T max ) and half‐life (t 1/2 ) are ~2 hours and ~15 hours, respectively, supporting once‐daily administration 7 . Doravirine may be administered without regard to food and possesses a favourable drug interaction profile, with no expected clinically relevant effects on the disposition of commonly co‐administered drugs 9‐17 . Being primarily eliminated via cytochrome P450 (CYP)3A4‐mediated hepatic metabolism, 18 meaningful reductions in doravirine exposure occur with moderate and strong CYP3A4 inducers 11 ; however, there is low interaction potential for other major drug‐metabolizing agents or transporters 14 …”