Pharmacokinetics and safety of boosted elvitegravir in subjects with hepatic impairment.

Elvitegravir (EVG), an HIV strand transfer integrase inhibitor, is metabolized primarily via cytochrome P450 3A4 (CYP3A) and secondarily via glucuronidation. The pharmacokinetics (PK) and safety of cobicistat (COBI)-boosted EVG (EVG/co) were evaluated in subjects with impaired liver function. The enrolled subjects had stable moderate liver impairment (n = 10; Child-Pugh-Turcotte [CPT] class B) or were healthy controls (n = 10) matched for age (±5 years), gender, and body mass index (±15%). EVG/co (150/150 mg) was administered once daily for 10 days, followed by pharmacokinetic (PK) sampling. Safety was assessed throughout the study. EVG and COBI exposures were compared between the impairment and control groups, with a ≥100% increase considered clinically relevant. EVG and COBI protein binding was also measured. All enrolled subjects completed the study. The treatment-emergent adverse event (AE) incidences were comparable between the groups; all study drug-related AEs were mild. The geometric mean ratio (90% confidence interval [CI]) for EVG area under the concentration-time curve over the dosing interval (AUCtau) and maximum observed plasma concentration (Cmax) were 135% (103%, 177%) and 141% (109%, 183%), respectively. The corresponding values for COBI were 99.8% (76.0%, 131%) and 86.1% (65.4%, 113%), respectively, indicating no clinically relevant change in exposure. No correlations were observed between the EVG and COBI exposures versus CPT score. The EVG- and COBI-free fractions were similar between groups. EVG and COBI do not require dose adjustment in moderate or mild liver impairment, as no clinically relevant PK changes were observed for EVG or COBI in this special population. No PK or safety data are available for EVG or COBI in subjects with severe hepatic impairment.

RCT Entities:   Population Interventions Outcomes