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. CONCLUSION: This pharmacokinetic-pharmacodynamic model successfully described the relation between plasma concentration of cilostazol and the antiplatelet and cardiovascular effects of the drug.
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. CONCLUSION: This pharmacokinetic-pharmacodynamic model successfully described the relation between plasma concentration of cilostazol and the antiplatelet and cardiovascular effects of the drug.
Authors: Norihiro Kato; Marie Loh; Fumihiko Takeuchi; Niek Verweij; Xu Wang; Weihua Zhang; Tanika N Kelly; Danish Saleheen; Benjamin Lehne; Irene Mateo Leach; Molly Scannell Bryan; Yik-Ying Teo; Jiang He; Paul Elliott; E Shyong Tai; Pim van der Harst; Jaspal S Kooner; John C Chambers; Alexander W Drong; James Abbott; Simone Wahl; Sian-Tsung Tan; William R Scott; Gianluca Campanella; Marc Chadeau-Hyam; Uzma Afzal; Tarunveer S Ahluwalia; Marc Jan Bonder; Peng Chen; Abbas Dehghan; Todd L Edwards; Tõnu Esko; Min Jin Go; Sarah E Harris; Jaana Hartiala; Silva Kasela; Anuradhani Kasturiratne; Chiea-Chuen Khor; Marcus E Kleber; Huaixing Li; Zuan Yu Mok; Masahiro Nakatochi; Nur Sabrina Sapari; Richa Saxena; Alexandre F R Stewart; Lisette Stolk; Yasuharu Tabara; Ai Ling Teh; Ying Wu; Jer-Yuarn Wu; Yi Zhang; Imke Aits; Alexessander Da Silva Couto Alves; Shikta Das; Rajkumar Dorajoo; Jemma C Hopewell; Yun Kyoung Kim; Robert W Koivula; Jian'an Luan; Leo-Pekka Lyytikäinen; Quang N Nguyen; Mark A Pereira; Iris Postmus; Olli T Raitakari; Robert A Scott; Rossella Sorice; Vinicius Tragante; Michela Traglia; Jon White; Ken Yamamoto; Yonghong Zhang; Linda S Adair; Alauddin Ahmed; Koichi Akiyama; Rasheed Asif; Tin Aung; Inês Barroso; Andrew Bjonnes; Timothy R Braun; Hui Cai; Li-Ching Chang; Chien-Hsiun Chen; Ching-Yu Cheng; Yap-Seng Chong; Rory Collins; Regina Courtney; Gail Davies; Graciela Delgado; Loi D Do; Pieter A Doevendans; Ron T Gansevoort; Yu-Tang Gao; Tanja B Grammer; Niels Grarup; Jagvir Grewal; Dongfeng Gu; Gurpreet S Wander; Anna-Liisa Hartikainen; Stanley L Hazen; Jing He; Chew-Kiat Heng; James E Hixson; Albert Hofman; Chris Hsu; Wei Huang; Lise L N Husemoen; Joo-Yeon Hwang; Sahoko Ichihara; Michiya Igase; Masato Isono; Johanne M Justesen; Tomohiro Katsuya; Muhammad G Kibriya; Young Jin Kim; Miyako Kishimoto; Woon-Puay Koh; Katsuhiko Kohara; Meena Kumari; Kenneth Kwek; Nanette R Lee; Jeannette Lee; Jiemin Liao; Wolfgang Lieb; David C M Liewald; Tatsuaki Matsubara; Yumi Matsushita; Thomas Meitinger; Evelin Mihailov; Lili Milani; Rebecca Mills; Nina Mononen; Martina Müller-Nurasyid; Toru Nabika; Eitaro Nakashima; Hong Kiat Ng; Kjell Nikus; Teresa Nutile; Takayoshi Ohkubo; Keizo Ohnaka; Sarah Parish; Lavinia Paternoster; Hao Peng; Annette Peters; Son T Pham; Mohitha J Pinidiyapathirage; Mahfuzar Rahman; Hiromi Rakugi; Olov Rolandsson; Michelle Ann Rozario; Daniela Ruggiero; Cinzia F Sala; Ralhan Sarju; Kazuro Shimokawa; Harold Snieder; Thomas Sparsø; Wilko Spiering; John M Starr; David J Stott; Daniel O Stram; Takao Sugiyama; Silke Szymczak; W H Wilson Tang; Lin Tong; Stella Trompet; Väinö Turjanmaa; Hirotsugu Ueshima; André G Uitterlinden; Satoshi Umemura; Marja Vaarasmaki; Rob M van Dam; Wiek H van Gilst; Dirk J van Veldhuisen; Jorma S Viikari; Melanie Waldenberger; Yiqin Wang; Aili Wang; Rory Wilson; Tien-Yin Wong; Yong-Bing Xiang; Shuhei Yamaguchi; Xingwang Ye; Robin D Young; Terri L Young; Jian-Min Yuan; Xueya Zhou; Folkert W Asselbergs; Marina Ciullo; Robert Clarke; Panos Deloukas; Andre Franke; Paul W Franks; Steve Franks; Yechiel Friedlander; Myron D Gross; Zhirong Guo; Torben Hansen; Marjo-Riitta Jarvelin; Torben Jørgensen; J Wouter Jukema; Mika Kähönen; Hiroshi Kajio; Mika Kivimaki; Jong-Young Lee; Terho Lehtimäki; Allan Linneberg; Tetsuro Miki; Oluf Pedersen; Nilesh J Samani; Thorkild I A Sørensen; Ryoichi Takayanagi; Daniela Toniolo; Habibul Ahsan; Hooman Allayee; Yuan-Tsong Chen; John Danesh; Ian J Deary; Oscar H Franco; Lude Franke; Bastiaan T Heijman; Joanna D Holbrook; Aaron Isaacs; Bong-Jo Kim; Xu Lin; Jianjun Liu; Winfried März; Andres Metspalu; Karen L Mohlke; Dharambir K Sanghera; Xiao-Ou Shu; Joyce B J van Meurs; Eranga Vithana; Ananda R Wickremasinghe; Cisca Wijmenga; Bruce H W Wolffenbuttel; Mitsuhiro Yokota; Wei Zheng; Dingliang Zhu; Paolo Vineis; Soterios A Kyrtopoulos; Jos C S Kleinjans; Mark I McCarthy; Richie Soong; Christian Gieger; James Scott Journal: Nat Genet Date: 2015-09-21 Impact factor: 38.330