Pharmacokinetic Comparison of Sustained- and Immediate-Release Oral Formulations of Cilostazol in Healthy Korean Subjects: A Randomized, Open-Label, 3-Part, Sequential, 2-Period, Crossover, Single-Dose, Food-Effect, and Multiple-Dose Study

• Published in: Clinical therapeutics 2011-12, Vol.33 (12), p.2038-2053
• Main Authors: Lee, Donghwan, MD, Lim, Lay Ahyoung, MD, Jang, Seong Bok, PhD, Lee, Yoon Jung, PhD, Chung, Jae Yong, MD, PhD, Choi, Jong Rak, MD, PhD, Kim, Kiyoon, MS, Park, Jin Woo, PhD, Yoon, Hosang, MS, Lee, Jaeyong, MS, Park, Min Soo, MD, PhD, Park, Kyungsoo, PhD, MD
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Area Under Curve; Asian Continental Ancestry Group; Cardiovascular Agents - administration & dosage; Cardiovascular Agents - adverse effects; Cardiovascular Agents - blood; Cardiovascular Agents - pharmacokinetics; Chemistry, Pharmaceutical; cilostazol; circadian variation; Clinical trials; Cross-Over Studies; Delayed-Action Preparations; Drug dosages; Female; Food; food effect; Food-Drug Interactions; Humans; Internal Medicine; Male; Medical Education; Metabolic Clearance Rate; Middle Aged; Models, Biological; multiple doses; Pharmaceuticals; pharmacokinetics; Prescription drugs; Product development; Republic of Korea; Studies; sustained-release; Tetrazoles - administration & dosage; Tetrazoles - adverse effects; Tetrazoles - blood; Tetrazoles - pharmacokinetics; Therapeutic Equivalency; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2011.10.024

Abstract Background A sustained-release (SR) formulation of cilostazol was recently developed in Korea and was expected to yield a lower Cmax and a similar AUC to the immediate-release (IR) formulation. Objective The goal of the present study was to compare the pharmacokinetic profiles of a newly developed SR formulation and an IR formulation of cilostazol after single- and multiple-dose administration and to evaluate the influence of food in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. Methods This was a randomized, 3-part, sequential, open-label, 2-period crossover study. Each part consisted of different subjects between the ages of 19 and 55 years. In part 1, each subject received a single dose of SR (200 mg × 1 tablet, once daily) and IR (100 mg × 2 tablets, BID) formulations of cilostazol orally 7 days apart in a fasted state. In part 2, each subject received a single dose of the SR (200 mg × 1 tablet, once daily) formulation of cilostazol 7 days apart in a fasted and a fed state. In part 3, each subject received multiple doses of the 2 formulations for 8 consecutive days 21 days apart. Blood samples were taken for 72 hours after the dose. Cilostazol pharmacokinetics were determined for both the parent drug and its metabolites (OPC-13015 and OPC-13213). Adverse events were evaluated through interviews and physical examinations. Results Among the 92 enrolled subjects (66 men, 26 women; part 1, n = 26; part 2, n = 26; part 3, n = 40), 87 completed the study. In part 1, all the primary pharmacokinetic parameters satisfied the criterion for assumed bioequivalence both in cilostazol and its metabolites, yielding 90% CI ratios of 0.9624 to 1.2323, 0.8873 to 1.1208, and 0.8919 to 1.1283 for Cmax and 0.8370 to 1.0134, 0.8204 to 0.9807, and 0.8134 to 0.9699 for AUC0–last of cilostazol, OPC-13015, and OPC-13213, respectively. In part 2, food intake increased Cmax and AUC significantly ( P < 0.0001), yielding geometric mean ratios of 3.2879, 2.9894, and 3.0592 for Cmax and 1.7001, 1.7689, and 1.6976 for AUC0–last of cilostazol, OPC-13015, and OPC-13213. In part 3, only the Cssmax of clilostazol in the reference formulation did not satisfy the criterion for assumed bioequivalence, yielding 90% CI ratios of 1.2693 to 1.4238 and 1.2038 to 1.3441, respectively. When each dose was normalized, the Cmax for the SR formulation was significantly lower ( P < 0.005 for cilostazol)