Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast.
OBJECTIVE
To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers.


METHODS
Clinical pharmacology unit.


METHODS
Five prospective pharmacokinetic studies: one single-blind, dose-escalating, placebo-controlled trial; four open-label, randomized studies.


METHODS
Ninety-six healthy adult volunteers who were nonsmokers.


METHODS
In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15-mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide.


RESULTS
After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose-proportional manner; the half-life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2-hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), 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 coadministration of antacid.


CONCLUSIONS
The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.
Zussman
B D
BD
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Parmaceutical, Welwyn, Herts, United Kingdom.
Davie
C C
CC
Kelly
J
J
Murdoch
R D
RD
Clark
D J
DJ
Schofield
J P
JP
Walls
C
C
Birrell
C
C
Webber
D
D
Quinlan
J
J
Ritchie
S Y
SY
Carr
A
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000863:Antacids / Q000008:administration & dosage; D019540:Area Under Curve; D001682:Biological Availability; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002264:Carboxylic Acids; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005502:Food; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009570:Nitriles
D000863:Antacids; D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4