Pharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy Volunteers

Abstract

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0–24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0–24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0–24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.

Comorbidities and concomitant medications in patients with chronic hepatitis C virus infection receiving second-generation direct-acting antiviral regimens in Belgium : an observational study

“…Drug-drug interactions have been reported between EBR/GZR and certain antiretroviral therapies for HIV infection. Increased GZR exposure has been reported when EBR/GZR is coadministered in combination with the fixed-dose combination of elvitegravir/cobicistat/ tenofovir disoproxil fumarate/emtricitabine (25) or with the ritonavir-boosted protease inhibitors atazanavir, lopinavir, and darunavir (26,27). Ledipasvir and velpatasvir have pH-dependent solubility, and therefore concomitant use of agents that increase gastric pH, such as proton-pump inhibitors and histamine H2 receptor antagonists, can reduce their bioavailability (28).…”

Review of Clinically Relevant Drug Interactions with Next Generation Hepatitis C Direct-acting Antiviral Agents

“…38 A pharmacokinetic study of GZR and rifampin in healthy volunteers found a significant decrease in C 24h of GZR after multiple oral rifampin doses, likely due to CYP3A4/P-gp induction by rifampin. 40 Combination of multiple doses of rifampin and SOF/VEL also led to a significant decrease in both SOF and VEL AUC by 72% and 82%, respectively. 18 Likewise, VOX AUC decreased by 73% when given with multiple doses of rifampin.…”

Clinically-driven design of synthetic gene regulatory programs in human cells

“…3D, Methods ). For mice receiving synZiFTR-controlled anti-Her2 CAR T cells, GZV was dosed every day at 25 mg/kg for 14 days, either alone or in combination with lopinavir/ritonavir (LPV/RTV, 10 mg/kg), an antiretroviral drug cocktail known to increase GZV bioavailability ( 61 ). Importantly, GZV inducer combinations have no effect on cells on their own ( Fig.…”