Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment

• Published in: Journal of hepatology Vol. 63; no. 4; pp. 805 - 812
• Main Authors: Khatri, Amit, Menon, Rajeev M., Marbury, Thomas C., Lawitz, Eric J., Podsadecki, Thomas J., Mullally, Victoria M., Ding, Bifeng, Awni, Walid M., Bernstein, Barry M., Dutta, Sandeep
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2015
• Subjects: Anilides - administration & dosage; Anilides - pharmacokinetics; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; Carbamates - administration & dosage; Carbamates - pharmacokinetics; Chronic hepatitis C; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics; Dasabuvir; Direct-acting antiviral agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gastroenterology and Hepatology; Hepatic impairment; Hepatic Insufficiency - blood; Hepatic Insufficiency - etiology; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - drug therapy; Humans; Liver Function Tests; Macrocyclic Compounds - administration & dosage; Macrocyclic Compounds - pharmacokinetics; Male; Middle Aged; Ombitasvir; Paritaprevir; Pharmacokinetics; Ribavirin - administration & dosage; Ribavirin - pharmacokinetics; Ritonavir; Ritonavir - administration & dosage; Ritonavir - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Treatment Outcome; Uracil - administration & dosage; Uracil - analogs & derivatives; Uracil - pharmacokinetics; LLOQ; NS; Ritonavir; SVR12; ALT; AUC; fu; ANCOVA; SD; Paritaprevir/r; Direct-acting antiviral agents; Ombitasvir; Hepatic impairment; t1/2; ULN; Paritaprevir; CYP; BMI; BCRP; Cmax; AST; P-gp; DAA; GT1; CI; Vβ/F; ECG; OATP; Dasabuvir; β; CV; Chronic hepatitis C; Tmax; HCV; Pharmacokinetics; CL/F; apparent volume of distribution; V β/F; alanine aminotransferase; apparent oral clearance; SVR 12; electrocardiogram; sustained virologic response 12 weeks post-treatment; lower limit of quantitation; breast cancer resistance protein; body mass index; T max; area under the plasma concentration-time curve; f u; analysis of covariance; standard deviation; organic anion transporting polypeptide; C max; nonstructural; direct-acting antiviral agent; hepatitis C virus; t 1/2; genotype 1; paritaprevir administered with ritonavir; terminal phase elimination half-life; time to maximum observed plasma concentration (C max); cytochrome P450; aspartate aminotransferase; P-glycoprotein; upper limit of normal; maximal plasma concentration; unbound fraction; confidence interval; apparent terminal phase elimination rate constant; coefficient of variation
• DOI: 10.1016/j.jhep.2015.05.029
• ISSN: 0168-8278

Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. HCV-negative subjects with normal hepatic function (n=7) or mild (Child-Pugh A, n=6), moderate (Child-Pugh B, n=6), or severe (Child-Pugh C, n=5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100mg), ombitasvir (25mg), and dasabuvir (400mg). Plasma samples were collected through 144hours after administration for pharmacokinetic assessments. Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, Cmax, and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.