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 + grazoprevir coadministration (N = 12), and trial 2 investigated the effect of single-dose doravirine and ledipasvir-sofosbuvir coadministration (N = 14). Doravirine had no clinically relevant effect on the pharmacokinetics of elbasvir, grazoprevir, ledipasvir, sofosbuvir, or the sofosbuvir metabolite GS-331007. Coadministration of elbasvir + 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 (C₂₄), 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 C₂₄ values increased slightly following coadministration with ledipasvir-sofosbuvir (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 + grazoprevir or ledipasvir-sofosbuvir was generally well tolerated. Clinically relevant DDIs are not expected to occur between doravirine and elbasvir-grazoprevir or ledipasvir-sofosbuvir at the therapeutic doses.

Keywords: HIV; doravirine; drug-drug interactions; nonnucleoside reverse transcriptase inhibitor (NNRTI).

FIG 1

Trial 1, elbasvir + grazoprevir, mean concentration-time profiles for doravirine, elbasvir, and grazoprevir. (A) Arithmetic mean (± standard deviation [SD]) doravirine plasma concentration versus time profiles following the administration of 100 mg doravirine once daily for 5 days alone and coadministered with 50 mg elbasvir and 200 mg grazoprevir once daily for 5 days in healthy adults (N = 12). (B and C) Arithmetic mean (±SD) elbasvir (B) and grazoprevir (C) plasma concentration versus time profiles following the administration of 50 mg elbasvir and 200 mg grazoprevir once daily for 10 days alone or coadministered with 100 mg doravirine once daily for 5 days in healthy adults (both N = 12). Main panels, linear scale; insets, semilog scale.

FIG 2

Trial 2, ledipasvir-sofosbuvir, mean concentration-time profiles for doravirine, ledipasvir, and sofosbuvir. (A) Arithmetic mean (± standard deviation [SD]) doravirine plasma concentration-time profiles following the administration of a single oral dose of 100 mg doravirine with and without the coadministration of a single oral dose of 90 mg ledipasvir and 400 mg sofosbuvir in healthy adults (N = 14). (B to D) Arithmetic mean (±SD) ledipasvir (B), sofosbuvir (C), and GS-331007 (D) plasma concentration-time profiles following the administration of a single oral dose of 90 mg ledipasvir with 400 mg sofosbuvir with and without the coadministration of a single oral dose of 100 mg doravirine in healthy adults (all N = 14). Main panels, linear scale; insets, semilog scale. Doravirine + ledipasvir-sofosbuvir linear profiles are shifted to the right for ease of reading.