The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor.
Antivir Ther
; 20(1): 29-37, 2015.
Article
en En
| MEDLINE
| ID: mdl-24704773
ABSTRACT
BACKGROUND:
It is necessary to evaluate the impact of hepatic impairment on the pharmacokinetic profile of direct-acting antiviral agents for the treatment of HCV infection.METHODS:
In this open-label, parallel group, multiple-dose study subjects (aged 18-70 years with a body mass index <35 kg/m(2)) with mild (n=6), moderate (n=6) and severe hepatic impairment (n=4) received asunaprevir 200 mg twice daily; healthy subjects (n=12) were matched (age, weight, gender) 11 to the first 4 subjects in each hepatic impairment group to act as controls. Pharmacokinetic sampling and analyses were performed on days 1 and 7 of dosing. Pharmacokinetic parameters were derived by non-compartmental methods. Geometric mean ratios (GMRs) and 90% CIs were used to assess the impact of hepatic impairment on the pharmacokinetics of asunaprevir, relative to healthy matched controls.RESULTS:
Compared with healthy subjects, mild hepatic impairment did not result in meaningful alterations in asunaprevir exposure (day 7 maximal plasma concentration [Cmax] GMR 0.58 [90% CI 0.35, 0.98]; area under the plasma concentration-time curve in one dosing interval [AUCtau] GMR 0.79 [90% CI 0.55, 1.15]); clinically significant increases in asunaprevir exposure were observed in subjects with moderate (Cmax GMR 5.03 [90% CI 2.99, 8.47]; AUCtau GMR 9.83 [90% CI 6.76, 14.28]) and severe hepatic impairment (Cmax GMR 22.92 [90% CI 12.57, 41.81]; AUCtau GMR 32.08 [90% CI 20.84, 49.40]). Correlation between increased asunaprevir exposure and all individual components of the Child-Pugh classification system was observed in subjects with moderate and severe hepatic impairment.CONCLUSIONS:
Mild hepatic impairment does not meaningfully affect the pharmacokinetic profile of asunaprevir. The dosing of asunaprevir in patients with moderate-to-severe hepatic impairment is not recommended. Clinicaltrials.gov identifier NCT01019070.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Inhibidores de Proteasas
/
Sulfonamidas
/
Hepacivirus
/
Hepatitis C Crónica
/
Isoquinolinas
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Límite:
Adolescent
/
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Antivir Ther
Asunto de la revista:
TERAPIA POR MEDICAMENTOS
/
VIROLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos