In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 63, No. 5 ( 2019-05)
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 ( 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 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.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.02491-18
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2019
detail.hit.zdb_id:
1496156-8
SSG:
12
SSG:
15,3
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