Abstract
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
(AUC0–36 or AUC0–∞, Cmax) 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/m2). Dalcetrapib exposure was increased by 64% (AUC0–36) and 126% (Cmax) 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/m2). When dalcetrapib was administered after a light morning or a light evening meal,
comparable values were found for mean dalcetrapib AUC0–∞ (7400 and 7860 ng · h/mL, respectively) and Cmax (589 and 552 ng/mL), whereas administration after a standard evening meal was associated
with increased AUC0–∞ (14.3%–14.7%) and Cmax (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/m2). Compared with administration after a standard evening meal, administration after
a high-fat evening meal was associated with increased AUC0–∞ (34.9%) and Cmax (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.
Key words
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Article info
Publication history
Accepted:
May 5,
2011
Identification
Copyright
© 2011 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
