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Τρίτη 19 Φεβρουαρίου 2019

Investigation of Pharmacokinetic Interactions Between Doravirine and Elbasvir/Grazoprevir and Ledipasvir/Sofosbuvir [Antiviral Agents]

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) co-infection, and co-administration 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 co-administration (N=12), and trial 2 investigated the effect of single-dose doravirine and ledipasvir/sofosbuvir co-administration (N=14). Doravirine had no clinically relevant effect on the pharmacokinetics of elbasvir, grazoprevir, ledipasvir, sofosbuvir, or the sofosbuvir metabolite GS-331007. Co-administration of elbasvir + grazoprevir with doravirine moderately increased doravirine area under the concentration–time curve from 0 to 24 hours (AUC0–24), maximal concentration (Cmax), and concentration 24 hours post-dose (C24) (geometric least-squares mean ratio [GMR], (90% confidence interval [CI]): 1.56 (1.45, 1.68), 1.41 (1.25, 1.58), and 1.61 (1.45, 1.79), respectively). Doravirine AUC0–, Cmax, and C24 values increased slightly following co-administration with ledipasvir/sofosbuvir (GMR (90% CI): 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. Co-administration 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.



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