Effect of Hepatic Impairment on the Pharmacokinetics of Dalcetrapib

Abstract

Synopsis: Dalcetrapib acts to raise high-density lipoprotein cholesterol (HDL-C) concentrations by reducing cholesteryl ester transfer protein (CETP) activity, with the expectation that increasing HDL-C will reduce cardiovascular risk. Patients with high cardiovascular risk often have comorbidities, and, because dalcetrapib is extensively metabolized, dose adjustment could be required in individuals with hepatic dysfunction. Purpose: To assess the effects of mild and moderate hepatic impairment on the pharmacokinetics of dalcetrapib to guide dosing recommendations for hepatically impaired patients. Methods: A multicenter, open-label, single dose study in adults (aged 18–70 years and BMI 18–40 kg/m2) with mild or moderate hepatic impairment (Child-Pugh A or B, respectively) and age- weight- and sex-matched controls with normal hepatic function. Eight patients were recruited into each hepatic impairment group, along with a total of 12 individuals with normal hepatic function. After oral administration of a single 600-mg dose of dalcetrapib, concentrations of dalcetrapib active form (DAL-AF) and inactive dalcetrapib-S-methyl (DAL-S-Me) and dalcetrapib-S-glucuronide (DAL-S-Glu) metabolites were measured in plasma and urine at intervals up to 96 hours after dosing. Safety was monitored throughout. Statistical comparisons of DAL-AF exposure parameters were made between hepatically impaired groups and matched controls. Results: DAL-AF exposure was similar for patients with mild impairment and matched controls; 90% confidence intervals (CIs) for comparisons of peak (Cmax) and total (AUCinf) exposure encompassed unity (Cmax GMR 0.828 [90% CI, 0.507−1.353]; AUCinf GMR 0.819 [90% CI, 0.519−1.291]). Other parameters for DAL-AF and metabolites were also comparable between the mild impairment and control groups. DAL-AF exposure was greater among patients with moderate impairment; Cmax and AUCinf of DAL-AF were 38% and 34% greater, respectively, than matched controls (Cmax GMR 1.381 [90% CI, 0.955−1.999]; AUCinf GMR 1.341 [90% CI, 1.020−1.762]). Exposure to DAL-S-Me and DAL-S-Glu metabolites also were greater in the moderate impairment group compared with the control group. DAL-AF and DAL-S-Me concentrations in urine were generally below assay quantification limits. DAL-S-Glu amounts in urine were negligible (<1% of dose) but were increased in moderate hepatic impairment (>2%). Hepatic impairment had no apparent effect on the safety profile of a single 600 mg dose. Conclusions: Dalcetrapib pharmacokinetics were comparable in subjects with and without mild hepatic impairment whereas moderate impairment provided modest increases in systemic exposures previously observed to be well tolerated. Dose adjustment of dalcetrapib is not anticipated in mild or moderate hepatic impairment.