Relative Bioavailability and Effects of a High Fat Meal on Single Dose Cilostazol Pharmacokinetics

Abstract

Objectives

The objectives of this research were to (1) assess the relative bioavailability following administration of a 100mg cilostazol suspension versus 100mg tablet; (2) assess dosage form equivalency (2 × 50mg compared with 1 × 100mg); (3) compare the relative bioavailability following a single 50mg dose of cilostazol administered as an ethanolic solution versus a 50mg tablet; and (4) determine the effects of high fat diet on the pharmacokinetics of cilostazol following a single dose of 100mg cilostazol in the fed or fasted state. Results were compiled from 3 separate studies to address these objectives.

Design

All studies involved healthy adult males receiving single oral doses of cilostazol in the fed or fasted state. The fed state consisted of administering cilostazol after ingestion of a high fat meal. One study compared the relative bioavailability of 100mg suspension and 2 × 50mg tablet versus 100mg tablet in a randomised crossover design. The study involving administration of a 50mg cilostazol ethanolic solution was a single treatment study. The effects of food on the pharmacokinetics of cilostazol after administration of 100mg cilostazol in the fed or fasted state as well as the pharmacokinetic profile following administration of a single 50mg oral dose of cilostazol were assessed in a randomised crossover design.

Study Participants

All participants were healthy nonsmoking males aged between 19 and 48 years whose bodyweight was within 15% of ideal bodyweight.

Main Outcome Measures

Noncompartmental pharmacokinetic parameters were determined for each study participant.

Results

The area under the plasma concentration-time curve (AUC) parameters were within the 80 to 125% criterion for bioequivalence for the cilostazol and its primary metabolite, OPC-13015. The maximum observed plasma concentrations (C_max) for these formulations were not equivalent and indicated that the absorption of cilostazol from a suspension is more rapid than from a tablet. The apparent terminal half-lives (t1/2_z) of cilostazol and OPC-13015 were shorter after administration of the suspension compared with the tablet. C_max and AUC following administration of a single 50mg cilostazol tablet were approximately 80% of that from the same dose administered as an ethanolic solution. The t1/2_z of cilostazol decreased from 15.5 hours after a tablet to 2.5 hours after an ethanolic solution. Upon coadministration with a high fat meal, the C_max of cilostazol increased 90% and AUC_∞ increased 25% (p < 0.05). The t1/2_z decreased from 15.1 ± 14.5 hours (mean ± SD) in the fasted state to 5.4 ± 2.0 hours in the fed state. Single oral doses of 50 and 100mg cilostazol were well tolerated.

Conclusions

The relative bioavailability of the 100mg cilostazol tablet versus an oral 100mg cilostazol suspension is 100%.The 2 × 50mg and 1 × 100mg tablets are considered to be bioequivalent. The absorption following administration of 50mg cilostazol ethanolic solution is faster and appears to be greater than that after administration of the 50mg tablet. Coadministration of food increases the rate and extent of cilostazol absorption. The oral pharmacokinetics of cilostazol and metabolites are absorption-rate limited. The significant differences in the t1/2_z observed when comparing cilostazol tablet, suspension, and solution as well as the effects of food suggest ‘flip-flop’ pharmacokinetics.