Potential interactions between cilostazol and probucol: a two-part, single-dose, open-label study in healthy Korean male volunteers.
BACKGROUND
Combined therapy with cilostazol, an antiplatelet agent, and probucol, an antihyperlipidemic agent, has been reported to prevent restenosis after percutaneous transluminal coronary angioplasty. However, the potential for pharmacokinetic drug interactions between the 2 agents has not been evaluated.


OBJECTIVE
The aims of this study were to compare the pharmacokinetic properties of cilostazol and probucol administered alone and together in healthy Korean male volunteers.


METHODS
This open-label study in healthy adult (age 20-40 years) male volunteers consisted of 2 parts. Part A had a 1-sequence, 2-period crossover design in which each subject received cilostazol 100 mg (1 tablet) in period 1 and cilostazol 100 mg (1 tablet) plus probucol 500 mg (2 tablets) in period 2. Part B had a parallel-group design in which one group received probucol 250 mg (1 tablet) and the other received probucol 250 mg (1 tablet) and cilostazol 100 mg (1 tablet). Geometric mean ratios for C(max) and AUC were compared by ANOVA, and pharmacokinetic parameters were also compared by t tests. Tolerability was evaluated based on adverse events, ECGs, vital signs, and clinical laboratory test results.


RESULTS
Twelve healthy volunteers completed part A; their mean age was 24.1 years (range, 21-29 years), mean height 171.8 cm (range, 163-177 cm), and mean weight 65.2 kg (range, 56.3-77.6 kg). Of the 20 healthy volunteers enrolled in part B, 19 completed the study; their mean age was 25.1 years (range, 21-34 years), mean height 173.2 cm (range, 162-183 cm), and mean weight 65.5 kg (54.0-78.0 kg). The pharmacokinetic parameters of cilostazol and probucol did not differ significantly when the 2 agents were administrated alone or together. In part A, the geometric mean ratios for C(max) and AUC(0-60h) between coadministration and single administration of cilostazol were 0.8882 (90% CI, 0.7873-1.002) and 1.013 (90% CI, 0.8643-1.188), respectively, for cilostazol; 0.8758 (90% CI, 0.7584-1.011) and 0.9785 (90% CI, 0.7600-1.260) for the OPC-13015 metabolite; and 0.8730 (90% CI, 0.7486-1.018) and 1.004 (90% CI, 0.8847-1.140) for the OPC-13213 metabolite. In part B, the geometric mean ratios for C(max) and AUC(0-648)h between coadministration and single administration of probucol were 1.134 (90% CI, 0.8177-1.572) and 1.070 (90% CI, 0.7364-1.555), respectively. Twenty-five adverse events were reported by 9 subjects in part A; the most frequently reported were headache (10 events) and nausea (4 events). Twenty adverse events were reported by 10 subjects in part B; the most frequently reported were headache (4 events) and productive cough (3 events). No clinically significant changes were noted in vital signs, ECGs, or laboratory values.


CONCLUSIONS
In these healthy Korean male volunteers, coadministration of single doses of cilostazol and probucol had no significant effects on the pharmacokinetics of either drug. ClinicalTrials.gov identifier: NCT00549978.
Kim
Kyu-pyo
KP
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Kim
Bo-Hyung
BH
Lim
Kyoung Soo
KS
Kim
Tae-Eun
TE
Shin
Sang-Goo
SG
Jang
In-Jin
IJ
Yu
Kyung-Sang
KS
D000328:Adult; D000924:Anticholesteremic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D000077407:Cilostazol; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D007723:Korea; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011341:Probucol / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013777:Tetrazoles / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
D000924:Anticholesteremic Agents; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol; D011341:Probucol