Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir

Abstract

Doravirine is a non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Due to the high prevalence of HIV-1 and hepatitis C virus (HCV) coinfection and coadministration of HIV-1 and HCV treatment, potential drug-drug interactions (DDIs) between doravirine and two HCV treatments were investigated in two phase 1 drug interaction trials in healthy participants. Trial 1 investigated the effect of multiple-dose doravirine and elbasvir ϩ grazoprevir coadministration (N ϭ 12), and trial 2 investigated the effect of single-dose doravirine and ledipasvir-sofosbuvir coadministration (N ϭ 14). Doravirine had no clinically relevant effect on the pharmacokinetics of elbasvir, grazoprevir, ledipasvir, sofosbuvir, or the sofosbuvir metabolite GS-331007. Coadministration of elbasvir ϩ grazoprevir with doravirine moderately increased doravirine area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ), maximal concentration (C max ), and concentration 24 h postdose (C 24 ), with geometric least-squares mean ratio (GMR) with 90% confidence intervals (CI) of 1.56 (1.45, 1.68), 1.41 (1.25, 1.58), and 1.61 (1.45, 1.79), respectively. Doravirine AUC 0 -∞ , C max , and C 24 values increased slightly following coadministration with ledipasvirsofosbuvir (GMR [90% CI] of 1.15 [1.07, 1.24], 1.11 [0.97, 1.27], and 1.24 [1.13, 1.36], respectively). The modest increases in doravirine exposure are not clinically meaningful based on the therapeutic profile of doravirine. Effects are likely secondary to cytochrome P450 3A and P-glycoprotein inhibition by grazoprevir and ledipasvir, respectively. Coadministration of doravirine with elbasvir ϩ grazoprevir or ledipasvirsofosbuvir was generally well tolerated. Clinically relevant DDIs are not expected to occur between doravirine and elbasvir-grazoprevir or ledipasvir-sofosbuvir at the therapeutic doses.

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.…”

“…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. 25 These previous findings support that doravirine is unlikely to cause DDIs with concomitant medications that may be administered for the treatment of comorbidities.…”

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.…”