Effects of food intake on the pharmacokinetic properties of dalcetrapib: findings from three phase I, single-dose crossover studies in healthy volunteers.

BACKGROUND: Preclinical studies have reported that the relative bioavailability of dalcetrapib, a modulator of cholesteryl ester transfer protein (CETP) inhibitor activity, was ∼60% higher when administered in the fed state compared with the fasting state.

OBJECTIVE: This article reports on 3 studies conducted to assess the effects of food intake, timing of administration with respect to meals, and meal size and content on the relative bioavailability of dalcetrapib in healthy male subjects.

METHODS: Three Phase I studies were performed in healthy subjects: (1) a 2-period crossover study of a single dose of dalcetrapib 900 mg administered in the fed and fasting states (fed versus fasting study [1999]); (2) a 3-period crossover study of a single dose of dalcetrapib 600 mg administered after a light morning meal, a standard evening meal, and a light evening meal (meal timing/size study [2005]); and (3) a 4-period crossover study of a single dose of dalcetrapib 600 mg administered 30 minutes after a high-fat meal or a standard evening meal, and 30 minutes before or 3 hours after the latter (high-fat meal study [2007]). Blood samples for pharmacokinetic analyses (AUC(0-36) or AUC(0-∞), C(max)) were collected up to 36, 144, and 96 hours after study drug administration in the fed versus fasting, meal timing/size, and high-fat meal studies, respectively. CETP activity was measured using a radioisotopic method in the fed versus fasting study and a fluorometric method in the meal timing/size and high-fat meal studies. Tolerability was assessed using monitoring of adverse events, laboratory parameters, vital signs, and ECG.

RESULTS: Six men were enrolled in the fed versus fasting study (mean age, 37 years; mean body mass index [BMI], 23.6 kg/m(2)). Dalcetrapib exposure was increased by 64% (AUC(0-36)) and 126% (C(max)) after administration in the fed state. Eighteen men were enrolled in the analysis of the effects of meal timing and size on the properties of dalcetrapib (mean age, 30.5 years; mean BMI, 25.1 kg/m(2)). When dalcetrapib was administered after a light morning or a light evening meal, comparable values were found for mean dalcetrapib AUC(0-∞) (7400 and 7860 ng·h/mL, respectively) and C(max) (589 and 552 ng/mL), whereas administration after a standard evening meal was associated with increased AUC(0-∞) (14.3%-14.7%) and C(max) (25.5%-35.3%). Forty-nine men were included in the analysis in the high-fat meal study (mean age, 32.3 years; mean BMI, 23.9 kg/m(2)). Compared with administration after a standard evening meal, administration after a high-fat evening meal was associated with increased AUC(0-∞) (34.9%) and C(max) (43.7%). Between-treatment differences in exposure within each study also were reflected in apparent differences in CETP activity. All treatments were generally well tolerated.

CONCLUSIONS: Dalcetrapib exposure was increased in the fed state and, to a lesser extent, was dependent on the size and fat content of the meal. Exposure was independent of dosing time. Dalcetrapib was generally well tolerated.