Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast

Study Objective. To determine the absolute bioavailability of cilomilast, a nd assess the effects of food, dosing time, and co administration of antaci d agents on its bioavailability and pharmacokinetics in healthy volunteers. Setting. Clinical pharmacology unit. Design. Five prospective pharmacokinetic studies: one single-blind, dose-es calating, placebo-controlled trial; four open-label, randomized studies. Su bjects. Ninety-six healthy adult volunteers who were nonsmokers. Intervention. In the first study, four subjects received intravenous cilomi last 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomil ast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a tot al of 76 subjects were given single oral 15-mg doses; one study compared it s effects in fed versus fasted subjects, one looked for differences of morn ing versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide. Measurements and Main Results. After intravenous administration of cilomila st, plasma concentrations increased in an approximately dose-proportional m anner; the half-life, approximately 6.5 hours, was dose independent. Cilomi last clearance and volume of distribution were small. After oral dosing, th e absolute bioavailability was consistently close to 100%. Absorption was s lower in fed subjects than in fasted (median 2-hr delay in time to reach ma ximum plasma concentration, average 39% reduction in maximum plasma concent ration), but the area under the concentration-time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or co administration of antacid. Conclusion. The absolute bioavailability of oral cilomilast was 100%; it wa s not adversely affected by time of dosing or coadministration with food or antacid.