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Background: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug–drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. Methods: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. Results: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. Conclusions: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR. [ABSTRACT FROM AUTHOR]

Purpose: To describe the phase 1 and population pharmacokinetic investigations that support dosing recommendations for elbasvir/grazoprevir (EBR/GZR) in hepatitis C virus-infected people with advanced chronic kidney disease. Methods: This was an open-label, two-part, multiple-dose trial (MK-5172 PN050; NCT01937975) in 24 non–HCV-infected participants with end-stage renal disease (ESRD) or severe renal impairment who received once-daily EBR 50 mg and GZR 100 mg for 10 days. Population pharmacokinetic analyses from the phase 3 C-SURFER study (PN052, NCT02092350) were also conducted. Results: When comparing haemodialysis (HD) and non-HD days in participants with ESRD, geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for EBR and GZR AUC0–24 were 1.14 (1.08–1.21) and 0.97 (0.87–1.09). When comparing ESRD and healthy participants, GMRs (90% CIs) for EBR and GZR AUC0–24 were 0.99 (0.75–1.30) and 0.83 (0.56–1.22) on HD days, and 0.86 (0.65–1.14) and 0.85 (0.58–1.25) on non-HD days. GMRs (90% CIs) for AUC0–24 in participants with severe renal impairment relative to healthy controls were 1.65 (1.09–2.49) for GZR and 1.86 (1.38–2.51) for EBR. In population modelling of data from C-SURFER, absolute geometric means of steady-state EBR AUC0–24 were 2.78 and 3.07 μM*h (HD and non-HD recipients) and GZR AUC0–24 were 1.80 and 2.34 μM*h (HD and non-HD recipients). Conclusions: EBR/GZR represents an important treatment option for HCV infection in people with severe renal impairment and those with ESRD. No dosage adjustment of EBR/GZR is required in people with any degree of renal impairment, including those receiving dialysis. [ABSTRACT FROM AUTHOR]

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single‐dose trial in healthy participants. Trial 2 was a multiple‐dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0‐∞ were 0.98 (0.89–1.08), 0.97 (0.86–1.09), and 0.88 (0.78–1.00) in the presence/absence of EBR; 0.98 (0.81–1.19), 1.13 (0.97–1.32), and 1.10 (0.82–1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0‐∞ in the absence/presence of BUP/NAL were 1.22 (0.98–1.52) and 0.86 (0.63–1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy. [ABSTRACT FROM AUTHOR]