Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor

Abstract

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multipledose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steadystate GZR AUC 0 -24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was Ϸ2-, Ϸ5-, or Ϸ12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection

“…Several other important considerations should be taken account when selecting a DAA regimen for these patients. Protease inhibitors should be avoided in the presence of moderate to severe liver dysfunction (i.e., Child‐Pugh B or C) . Assessment of drug–drug interactions is crucial as some medications are contraindicated or not recommended during DAA therapy (e.g., high‐dose proton pump inhibitors [twice daily dosing], amiodarone [contraindicated with sofosbuvir‐inclusive regimens], and certain statins [e.g., atorvastatin], among others).…”

Drug–Drug Interactions of Newly Approved Direct-Acting Antiviral Agents in Patients with Hepatitis C

“… 5 Furthermore, as both drugs are metabolized by the liver, they are prohibited in patients with moderate and severe liver injury (Child-Pugh B or C). 26 The peak plasma concentration is attained in 3 h for elbasvir and 2 h for grazoprevir. Elbasvir binds to plasma proteins at a rate of 99.9% and grazoprevir binds to plasma proteins at a rate of 98.8%.…”

Eligibility of the prognostic systems in assessing the severity of liver cirrhosis

“…(2017 г.) сранивали фармакокинетику гразопревира у больных циррозом печени всех функциональных классов (А, В и С, вплоть до 12 баллов по Чайлд-Пью) и здоровых добровольцев, причем все больные, включенные в исследование, не были инфицированы HCV [26]. Пациенты принимали 200 мг, 100 мг или 50 мг гразопревира в течение 10 дней.…”