Population Pharmacokinetics of Glecaprevir/Pibrentasvir in HCV-infected Japanese Subjects in Phase 3 CERTAIN-1 and CERTAIN-2 Trials

• Published in: Journal of clinical pharmacology Vol. 60; no. 3; p. 331
• Main Authors: Suleiman, Ahmed Abbas, Lin, Chih-Wei, Liu, Wei, Eckert, Doerthe, Mensing, Sven, Burroughs, Margaret, Kato, Koji, Chayama, Kazuaki, Kumada, Hiromitsu, Oberoi, Rajneet K
• Format: Journal Article
• Language: English
• Published: England 01.03.2020
• Subjects: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Aminoisobutyric Acids - administration & dosage; Aminoisobutyric Acids - adverse effects; Aminoisobutyric Acids - pharmacokinetics; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Area Under Curve; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - pharmacokinetics; Biological Availability; Body Weight; Cyclopropanes - administration & dosage; Cyclopropanes - adverse effects; Cyclopropanes - pharmacokinetics; Drug Administration Schedule; Drug Combinations; Female; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - drug therapy; Humans; Japan; Lactams, Macrocyclic - administration & dosage; Lactams, Macrocyclic - adverse effects; Lactams, Macrocyclic - pharmacokinetics; Leucine - administration & dosage; Leucine - adverse effects; Leucine - analogs & derivatives; Leucine - pharmacokinetics; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Male; Middle Aged; Models, Biological; Proline - administration & dosage; Proline - adverse effects; Proline - analogs & derivatives; Proline - pharmacokinetics; Quinoxalines - administration & dosage; Quinoxalines - adverse effects; Quinoxalines - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Young Adult; Japan; hepatitis C virus; glecaprevir/pibrentasvir; Japanese; direct-acting antivirals; population pharmacokinetics
• ISSN: 1552-4604
• DOI: 10.1002/jcph.1524

Glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (Mavyret/Maviret) is an all-oral, pangenotypic, interferon- and ribavirin-free combination regimen approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the current analyses was to characterize the pharmacokinetics (PK) of GLE/PIB in HCV-infected Japanese patients. Data from 332 subjects enrolled in 2 Japan phase 3 trials, CERTAIN-1 and CERTAIN-2, were used in the analyses. Pharmacokinetics of GLE/PIB were characterized using a nonlinear mixed-effects modeling. The analyses evaluated the impact of covariates (concomitant medications and demographic and clinical covariates such as renal impairment, effect of cirrhotic status) on GLE/PIB PK. GLE and PIB PK were described by 1- and 2-compartment models, respectively. Presence of cirrhosis, age, and body weight were identified as significant covariates on GLE/PIB PK. A trend toward higher GLE and PIB exposures in older patients and higher PIB exposures in heavier patients was observed; however, these increases were not considered clinically meaningful. GLE and PIB exposures were higher in HCV-infected subjects with cirrhosis (Child-Pugh A; GLE area under the plasma concentration-time curve was 160% higher, and PIB area under the plasma concentration-time curve was 21% higher) compared to subjects without cirrhosis. Renal function (including subjects with end-stage renal disease with dialysis) had no impact on GLE or PIB exposures. The GLE/PIB dose was well tolerated in the Japanese population, and no dose adjustment is needed for the evaluated intrinsic and extrinsic factors.