Population Pharmacokinetic Analysis of Simvastatin and its Active Metabolite with the Characterization of Atypical Complex Absorption Kinetics

详细信息    查看全文

• 作者：Seok-Joon Jin (2)
  Kyun-Seop Bae (1)
  Sang-Heon Cho (3)
  Jin-Ah Jung (4)
  Unjib Kim (1)
  Sangmin Choe (5)
  Jong-Lyul Ghim (6)
  Yook-Hwan Noh (6)
  Hyun-Jung Park (7)
  Hee-sun Kim (8)
  Hyeong-Seok Lim (1)
  
• 关键词：absorption model ; multiple peaks ; NONMEM ; simvastatin ; simvastatin acid
• 刊名：Pharmaceutical Research
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：31
• 期：7
• 页码：1801-1812
• 全文大小：
• 参考文献：1. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, / et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A. 1980;77:3957-1. CrossRef
  2. Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH, / et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30:505-2. CrossRef
  3. Prueksaritanont T, Qiu Y, Mu L, Michel K, Brunner J, Richards KM, / et al. Interconversion pharmacokinetics of simvastatin and its hydroxy acid in dogs: effects of gemfibrozil. Pharm Res. 2005;22:1101-. CrossRef
  4. Merck Sharpe & Dohme. Manufacturer Information, Zocor: simvastatin. PA: West Point; 1991.
  5. Kim J, Ahn BJ, Chae HS, Han S, Doh K, Choi J, / et al. A Population Pharmacokinetic-PharmacodynamicModel for Simvastatin that Predicts Low-Density Lipoprotein-Cholesterol Reduction in Patients with Primary Hyperlipidaemia. Basic Clin Pharmacol Toxicol. 2011;109:156-3. CrossRef
  6. Mahmood I. Pharmacokinetic analysis of the absorption characteristics of diclofenac sodium in man by use of a multi-segment absorption model. J Pharm Pharmacol. 1996;48:1260-. CrossRef
  7. Huang SM, Marriott TB, Weintraub HS, Arnold JD, Boccagno J, Abels R, / et al. Clinical pharmacokinetics of etintidine. Biopharm Drug Dispos. 1988;9:477-6. CrossRef
  8. Lee SH, Lee MG, Kim ND. Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to rats: absorption from various GI segments. J Pharmacokinet Biopharm. 1994;22:1-7. CrossRef
  9. Dixon R, Warrander A. The clinical pharmacokinetics of zolmitriptan. Cephalalgia. 1997;17 Suppl 18:15-0.
  10. Ezzet F, Krishna G, Wexler DB, Statkevich P, Kosoglou T, Batra VK. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther. 2001;23:871-5. CrossRef
  11. Funaki T. Enterohepatic circulation model for population pharmacokinetic analysis. J Pharm Pharmacol. 1999;51:1143-. CrossRef
  12. Plusquellec Y, Efthymiopoulos C, DuthilP HG. A pharmacokinetic model for multiple sites discontinuous gastrointestinal absorption. Med Eng Phys. 1999;21:525-2. CrossRef
  13. Lennernas H, Regardh CG. Dose-dependent intestinal absorption and significant intestinal excretion (exsorption) of the beta-blocker pafenolol in the rat. Pharm Res. 1993;10:727-1. CrossRef
  14. Oberle RL, Amidon GL. The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon. J Pharmacokinet Biopharm. 1987;15:529-4. CrossRef
  15. Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34:711-6. CrossRef
  16. Murata K, Noda K, Kohno K, Samejima M. Pharmacokinetic analysis of concentration data of drugs with irregular absorption profiles using multi-fraction absorption models. J Pharm Sci. 1987;76:109-3. CrossRef
  17. Wade JR, Kelman AW, Howie CA, Whiting B. Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis. J Pharmacokinet Biopharm. 1993;21:209-2. CrossRef
  18. Jemal M, Ouyang Z, Powell ML. Direct-injection LC-MS-MS method for high-through put simultaneous quantitation of simvastatin and simvastatin acid in human plasma. J Pharm Biomed Anal. 2000;23:323-0. CrossRef
  19. Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. J Pharmacokinet Pharmacodyn. 2003;30:387-04. CrossRef
  20. Ette EI, Williams PJ. Pharmacometrics: The Science of Quantitative Pharmacology. New York: Wiley-Interscience; 2007. CrossRef
  21. Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm. 1993;21:735-0. CrossRef
  22. Vickers S, Duncan CA, Chen IW, Rosegay A, Duggan DE. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos. 1990;18:138-5.
  23. Miller R. Pharmacokinetics and bioavailability of ranitidine in humans. J Pharm Sci. 1984;73:1376-. CrossRef
  24. Ogasawara A, Utoh M, Nii K, Ueda A, Yoshikawa T, Kume T, / et al. Effect of oral ketoconazole on oral and intravenous pharmacokinetics of simvastatin and its acid in cynomolgus monkeys. Drug Metab Dispos. 2009;37:122-. CrossRef
  25. Murtaza G. Solubility enhancement of simvastatin: a review. Acta Pol Pharm. 2012;69:581-0.
  
• 作者单位：Seok-Joon Jin (2)
  Kyun-Seop Bae (1)
  Sang-Heon Cho (3)
  Jin-Ah Jung (4)
  Unjib Kim (1)
  Sangmin Choe (5)
  Jong-Lyul Ghim (6)
  Yook-Hwan Noh (6)
  Hyun-Jung Park (7)
  Hee-sun Kim (8)
  Hyeong-Seok Lim (1)
  
  2. Department of Anesthesiology, Ulsan University College of Medicine Asan Medical Center, Pungnap-2-dong, 88 Olympic-ro 43-gil, Sonpa-gu, Seoul, 138-736, Korea
  1. Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, 88 Olympic-ro 43-gil, Sonpa-gu, Seoul, 138-736, Korea
  3. Department of Clinical Pharmacology, Inha University Hospital Inha University School of Medicine, Incheon, Republic of Korea
  4. Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea
  5. Division of Clinical Pharmacology, Clinical Trials Center, Pusan National University Hospital, Busan, Republic of Korea
  6. Department of Pharmacology, Inje University College of Medicine, Busan, Republic of Korea
  7. Pharmacokinetic & Pharmacogenetic Laboratory Clinical Research Center, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea
  8. Daewoong Pharmaceutical Company, Seoul, Republic of Korea
  
• ISSN：1573-904X

文摘

Purpose The pharmacokinetics of simvastatin is complex with multiple peaks in the absorption phase, which cannot be adequately described by a conventional first order absorption model. The biotransformation of simvastatin into simvastatin acid, an active metabolite, is reversible. This study evaluated the pharmacokinetics of simvastatin and simvastatin acid, focusing on the absorption kinetics. Methods Data were collected from three bioequivalence studies, in which subjects were administered 60?mg simvastatin, and from one crossover study, in which subjects were administered two doses randomly selected from 10, 20, 30, 40 to 80?mg simvastatin with washout period. The pharmacokinetics of simvastatin was assessed in 133 healthy males. Plasma concentrations of simvastatin and simvastatin acid were measured in 2,182 and 2,130 samples, respectively, and the pharmacokinetic data were analyzed using NONMEM. Results The time course of changes in the plasma simvastatin concentration was best described by a two-compartment linear model with three parallel absorption processes, each of which consisted of mixed zero-and first order absorption. Additions of inter-occasional variability to the absorption parameters significantly improved the model’s fit. The disposition parameter estimates were significantly different when different absorption models were applied, indicating the importance of the appropriate absorption modeling. Pharmacokinetic modeling preferred the inter-conversion between simvastatin and simvastatin acid. Conclusion A pharmacokinetic model describing the complex, multiple peak, absorption kinetics of simvastatin was formulated using three parallel, mixed zero and first-order absorptions. This type of absorption model may be applicable to other drugs that show irregular, multiple-peak concentrations during their absorption phase.