Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans.
OBJECTIVE
Cilostazol is an antiplatelet agent with vasodilating properties. It has been used to treat patients with peripheral ischemia, such as intermittent claudication. We used a pharmacokinetic-pharmacodynamic model to analyze the relation between the plasma concentration of cilostazol, the inhibitory effect of the drug on platelet aggregation, and the cardiovascular effects of the drug on healthy humans.


METHODS
A single oral dose of 100 mg cilostazol was administered to 20 healthy volunteers. Serial blood sampling and pharmacodynamic measurements were performed up to 48 hours thereafter. The effects of cilostazol on platelet aggregation, blood pressure, and heart rate were measured during the same period. The plasma concentration of cilostazol was measured with a validated HPLC method that entailed ultraviolet detection. The time courses of plasma cilostazol concentration, platelet aggregation, and cardiovascular effects were analyzed by means of pharmacokinetic-pharmacodynamic modeling with the program ADAPT II.


RESULTS
The plasma concentration-time course followed a 2-compartment model. Mean peak concentration was 775 ng/ml approximately 3.65 hours after administration of cilostazol. The maximal effect on platelet aggregation was a 31.14% reduction 6.05 hours after administration. No significant difference in systolic blood pressure was found. The maximal increase in heart rate was 13.49%, whereas the maximal decrease in diastolic blood pressure was 29.51%. Both peak effects were detected approximately 6 hours after administration of the drug. Platelet aggregation and cardiovascular effects (change in diastolic blood pressure and heart rate) were analyzed with the effect-link sigmoid maximal effect model.


CONCLUSIONS
This pharmacokinetic-pharmacodynamic model successfully described the relation between plasma concentration of cilostazol and the antiplatelet and cardiovascular effects of the drug.
Woo
Su Kyung
SK
College of Pharmacy, Chungnam National University, Taejeon, Korea.
Kang
Won Ku
WK
Kwon
Kwang-il
KI
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D000077407:Cilostazol; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008955:Models, Cardiovascular; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D000077407:Cilostazol