Effect of cilostazol on the pharmacokinetics and pharmacodynamics of warfarin.
OBJECTIVE
To evaluate the effect of cilostazol administration on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg dose of warfarin.


METHODS
A randomised double-blind 2-period crossover with healthy volunteers receiving either 100 mg cilostazol twice daily for 13 days or matching placebo twice daily for 13 days, and the other treatment 21 days later. A single 25 mg dose of warfarin was given 14 days prior to the start of the study, and 7 days after the cilostazol and placebo treatments.


METHODS
15 normal healthy male volunteers.


METHODS
Noncompartmental pharmacokinetic parameters for (R)- and (S)-warfarin, the area under the curve of the prothrombin time (AUCPT), activated partial thromboplastin time (AUCaPTT), Ivy bleeding times, unbound fraction (fu) of cilostazol, and warfarin were determined for each individual.


RESULTS
For (R)- and (S)-warfarin, the 90% confidence intervals for the ratios of the geometric means (90% CI) of the maximum plasma concentration and area under the plasma concentration-time curve were between 0.88 to 1.03. The 90% CI for the AUCPT and AUCaPTT was between 0.95 and 1.06. For Ivy bleeding time, the 90% CI for the ratios of the geometric means ranged between 0.71 and 1.22. The fu of cilostazol did not differ significantly between the 2 treatments. There was a 17% increase in the fu of warfarin (p < 0.05), which was not clinically significant.


CONCLUSIONS
Coadministration of warfarin with twice daily administration of cilostazol 100 mg did not alter (R)- and (S)-warfarin pharmacokinetics, prothrombin time, partial thromboplastin time, Ivy bleeding times, or cilostazol protein binding.
Mallikaarjun
S
S
Department of Clinical Pharmacokinetics/Pharmacodynamics & Metabolism, Otsuka America Pharmaceutical, Inc., Rockville, MD 20850, USA. steveb@mocr.oapi.com
Bramer
S L
SL
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D000077407:Cilostazol; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D013237:Stereoisomerism; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000925:Anticoagulants; D013777:Tetrazoles; D014665:Vasodilator Agents; D014859:Warfarin; D000077407:Cilostazol