Journal of Korean Society for Clinical Pharmacology and Therapeutics (임상약리학회지)

Korean Society for Clinical Pharmacology and Therapeutics (대한임상약리학회)
권호 표지

Comparison of Pharmacokinetics and Safety Between Coadministration of Cilostazol and Ginkgo Biloba Extract and Administration of a Fixed-Dose Combination

실로스타졸과 은행엽 엑스의 복합제 투여 및 병용투여시 약동학적 특성 및 안전성 비교

  • Jeon, Hye-Won (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Yi, So-Jeong (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Kim, Sung-Eun (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Kim, Bo-Hyung (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Lim, Kyoung-Soo (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Lee, Bong-Yong (Life Science R&D Center, SK Chemicals Co., Ltd) ;
  • Yu, Kyung-Sang (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Shin, Sang-Goo (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Jang, In-Jin (Department of Pharmacology and Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital)
  • 전혜원 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과) ;
  • 이소정 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과) ;
  • 김성은 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과) ;
  • 김보형 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과) ;
  • 임경수 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과) ;
  • 이봉용 (SK 케미칼) ;
  • 유경상 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과) ;
  • 신상구 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과) ;
  • 장인진 (서울대학교 의과대학 약리학교실 및 서울대학교병원 임상약리학과)
  • Received : 2010.02.09
  • Accepted : 2010.04.30
  • Published : 2010.06.30
⟨ Previous Next ⟩

Abstract

Background: Cilostazol is widely used as an antiplatelet drug in patients with intermittent claudication and peripheral arterial disease. Ginkgo biloba extract is prescribed in the management of circulatory disorders in peripheral arteries. Thus a fixed-dose combination of the two drugs has been under clinical development. The pharmacokinetics of cilostazol and safety profiles were compared between coadministration of cilostazol and Ginkgo biloba extract, and that of a fixed-dose combination of the two drugs. Methods: A randomized, open-label, single-dose, two-treatment, two-period, two-sequence crossover study was conducted in 26 healthy male volunteers. Subjects were administered cilostazol 100 mg and Ginkgo biloba extract 80 mg concomitantly and a fixed-dose combination of the two drugs with a 7-day washout in between. Plasma concentrations of cilostazol were determined by liquid chromatography-tandem mass spectrometry. Safety profiles were assessed by physical examinations, electrocardiograms, vital signs, laboratory testings, and monitoring adverse events. Results: Median $T_{max}$ of cilostazol was 3.0 and 4.0 hours after administration of cilostazol and Ginkgo biloba extract concomitantly and fixed-dose combination of the two drugs, respectively. The geometric mean ratio (90% confidence intervals) of the fixed dose combination to the coadministration for $C_{max}$ was 0.95 (0.87-1.05) and that for $AUC_{last}$ was 1.03 (0.96-1.10). The most frequently reported adverse event was headache, reported by 14 subjects. There was no difference of adverse event occurrences between two treatment groups. No serious adverse events were reported. Conclusion: Pharmacokinetics of cilostazol and safety were comparable between coadministration of cilostazol and Ginkgo biloba extract, and administration of a fixed-dose combination of the two drugs.

Keywords

Acknowledgement

Supported by : 서울대학교병원

References

  1. Igawa T, Tani T, Chijiwa T, Shiragiku, T, Shimidzu, S, Kawamura, K, Kato, S, Unemi, F, Kimura, Y. Potentiation of anti-platelet aggregating activity of cilostazol with vascular endothelial cells. Thromb Res, 1990;57:617-623. https://doi.org/10.1016/0049-3848(90)90079-R
  2. Chapman TM, Goa KL. Cilostazol: a review of its use in intermittent claudication. Am J Cardiovasc Drugs, 2003;3:117-138. https://doi.org/10.2165/00129784-200303020-00006
  3. Spinnewyn B, Blavet N, Clostre F, Bazan N, Braquet P. Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in Mongolian gerbils. Prostaglandins, 1987;34:337-349. https://doi.org/10.1016/0090-6980(87)90079-7
  4. Birks J, Grimley EV, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002:CD003120.
  5. Jacobs BP, Browner WS. Ginkgo biloba: a living fossil. Am J Med, 2000;108:341-342. https://doi.org/10.1016/S0002-9343(00)00290-4
  6. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J Clin Pharmacol, 1992;34:352-358. https://doi.org/10.1111/j.1365-2125.1992.tb05642.x
  7. Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA, Schoenberger NE. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil, 2000;81:668-678.
  8. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. Geneva: WHO Technical Report Series, No. 937; 2006.
  9. Guidelines for registration of fixed-dose combination medicinal products. Geneva: WHO Technical Report Series, No.929; 2005.
  10. Ryu KH, Han HY, Lee SY, Jeon SD, Im GJ, Lee BY, Kim K, Lim KM, Chung JH. Ginkgo biloba extract enhances antiplatelet and antithrombotic effects of cilostazol without prolongation of bleeding time. Thromb Res, 2009;124:328-334. https://doi.org/10.1016/j.thromres.2009.02.010
  11. Bramer SL, Forbes WP, Mallikaarjun S. Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease. Clin Pharmacokinet, 1999;37 Suppl 2:1-11. https://doi.org/10.2165/00003088-199937002-00001
  12. Pletal${\circledR}$ (NDA 20-863/S-021) Drug Label. In: OTSUKA; 2007.
  13. Birk S, Kruuse C, Petersen KA, Tfelt-Hansen P, Olesen J. The headache-inducing effect of cilostazol in human volunteers. Cephalalgia, 2006;26:1304-309. https://doi.org/10.1111/j.1468-2982.2006.01218.x
  14. Kim TE, Kim BH, Kim J, Kim KP, Yi S, Shin HS, Lee YO, Lee KH, Shin SG, Jang IJ, Yu KS. Comparison of the pharmacokinetics of ticlopidine between administration of a combined fixed-dose tablet formulation of ticlopidine 250 mg/ginkgo extract 80 mg, and concomitant administration of ticlopidine 250-mg and ginkgo extract 80-mg tablets: an open-label, two-treatment, single-dose, randomized-sequence crossover study in healthy Korean male volunteers. Clin Ther, 2009;31:2249-2257. https://doi.org/10.1016/j.clinthera.2009.10.011