Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China  

作　　者：Ke-hua WU Tao GUO Chen-hui DENG Zheng GUAN Liang LI Tian-yan ZHOU Wei LU 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs(Peking University),Beijing 100191,China [2]Department of Pharmaceutics,School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 100191,China [3]Department of Medicine,University of Chicago,Chicago 60616,USA [4]Department of Pharmacy,Shenyang Northern Hospital,Shenyang 110016,China

出　　处：《Acta Pharmacologica Sinica》2012年第11期1401-1408,共8页中国药理学报（英文版）

摘　　要：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 modafinJl 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 modaflnil, 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 （I/h） and 2.73 （I）, 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 adminis- tered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered.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 modafinJl 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 modaflnil, 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 （I/h） and 2.73 （I）, 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 adminis- tered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered.

关 键 词：MODAFINIL modafinil acid ETHNICITY ethnic group in China population pharmacokinetics NONMEM drug metabolism ESTERASE amidaset 

分 类 号：O357.1[理学—流体力学] S859.796[理学—力学]