Abstract
Aim:
To describe the population pharmacokinetic profile of modafinil acid and to compare the extent of metabolism of modafinil into modafinil acid in 5 major ethnic groups (Han, Mongolian, Korean, Uygur, and Hui) of China.
Methods:
In a multi-center, open-label, single dose clinical trial, 49 healthy volunteers from the 5 ethnic groups received 200 mg of modafinil orally. Blood samples for pharmacokinetic evaluation of modafinil and modafinil acid were drawn before and at different time after the administration. Systematic population pharmacokinetic (PopPK) modeling for modafinil acid was conducted, integrating with our previous PopPK model for modafinil. The influence of ethnicity, gender, height, body weight and body mass index (BMI) was estimated. The extent of metabolism of modafinil into modafinil acid, expressed as the relative conversion fraction, was estimated and compared among the 5 ethnic groups.
Results:
When combined with the PopPK model of modafinil, the concentration of modafinil acid versus time profile was best described with a one-compartment model. The typical clearance and volume of distribution for modafinil acid were 4.94 (l/h) and 2.73 (l), respectively. The Korean group had 25% higher clearance, and the Uygur and Hui groups had 12% higher clearance than the Han group. The median for the relative conversion fraction was 0.53 for Koreans, and 0.24 for the other 4 ethnicities.
Conclusion:
Ethnicity has significant influence on the clearance of modafinil acid. When patients in the 5 ethnic groups are administered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered.
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References
Minzenberg MJ, Carter CS . Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 2008; 33: 1477–502.
Wisor JP, Dement WC, Aimone L, Williams M, Bozyczko-Coyne D . Armodafinil, the R-enantiomer of modafinil: Wake-promoting effects and pharmacokinetic profile in the rat. Pharmacol Biochem Behav 2006; 85: 492–9.
Robertson P Jr, Hellriegel ET . Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet 2003; 42: 123–37.
Guengerich FP . Oxidative, reductive, and hydrolytic metabolism of drugs. In: Zhang DL, Zhu M, Humphreys WG, editors. Drug Metabolism in Drug Design and Development. USA: Wiley; 2008. p 29–31.
Coleman M . Conjugation and transport processes. In: Coleman M, editor. Human Drug Metabolism: An Introduction. London: Wiley-Blackwell; 2010. p 152.
Tao G, Longshan Z, Kehua W, Dongya X, Wei L, Zheng G, et al. Population pharmacokinetics of Modafinil in Chinese Han, Mongolian, Korean, Uygur, and Hui healthy subjects determined by nonlinear mixed-effects modeling. Ther Drug Monit 2010; 32: 189–93.
Nedderman A, Walker D . Metabolite testing in drug development. In: Bonate PL, Howard DR, editors. Pharmacokinetics in Drug Development: Advances and Applications, V 3. USA: Springer; 2011. p 134.
Zhao LS, Xia DY, Guo T . RP-HPLC determination of modafinil and modafinil acid in human plasma. Chin J Pharm anal 2008; 27: 1863–6.
Beal SL, Sheiner LB . NONMEM Users Guides. San Francisco, University of California, 1998.
Lehr T, Staab A, Tillmann C, Trommeshauser D, Raschig A, Schaefer HG, et al. Population pharmacokinetic modeling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease. Br J Clin Pharmacol 2007; 64: 36–48.
Mandema JW, Verotta D, Sheiner LB . Building population pharmacokinetic-pharmacodynamic models. I. Models for covariate effects. J Pharmacokinet Biopharm 1992; 20: 511–28.
Yano Y, Beal SL, Sheiner LB . Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 2001; 28: 171–92.
Karlsson MO, Holford N . A tutorial on visual predictive checks. Presented at: Annual meeting of the population approach group in Europe (PAGE); June 18–20, 2008: Marseille, Frence.
Weiss M . Drug metabolite kinetics: noncompartmental analysis. Br J Clin Pharmacol 1985; 19: 855–6.
FDA. FDA guidance for industry. Safety testing of drug metabolites. 2008. http://www.fda.gov/cder/guidance/6897fnl.pdf.
Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Järvinen T, et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 2008; 7: 255–70.
Ettmayer P, Amidon GL, Clement B, Testa B . Lessons learned from market and investigational prodrugs. J Med Chem 2004; 47: 2393–404.
Tian C, Kosoy R, Lee A, Ransom M, Belmont JW, Gregersen PK, et al. Analysis of East Asia genetic substructure using genome-wide SNP arrays. PLoS One 2008; 3: e3862.
Xu P, Li HD, Zhang BK, Xiao YW, Yuan HY, Zhu YG . Pharmacokinetics and tolerability of modafinil tablets in Chinese subjects. J Clin Pharm Ther 2008; 33: 429–37.
Ahn JE, Karlsson MO, Dunne A, Ludden TM . Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn 2008; 35: 401–21.
Seng KY, Fan L, Lee HS, Yong WP, Goh BC, Lee LS . Population pharmacokinetics of modafinil and its acid and sulfone metabolites in Chinese males. Ther Drug Monit 2011; 33: 719–29.
Cosson V, Jorga K, Fuseau E . Modeling of metabolite pharmacokinetics. in: Williams PJ, Ette EI, editors, Pharmacometrics: The Science of Quantitative Pharmacology. USA: Wiley;2007.p 1108.
Acknowledgements
We thank Long-shan ZHAO and Dong-ya XIA for collecting data for this study.
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Wu, Kh., Guo, T., Deng, Ch. et al. Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China. Acta Pharmacol Sin 33, 1401–1408 (2012). https://doi.org/10.1038/aps.2012.124
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DOI: https://doi.org/10.1038/aps.2012.124
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