Population Pharmacokinetics of Modafinil in Chinese Han, Mongolian, Korean, Uygur, and Hui Healthy Subjects Determined by Nonlinear Mixed-Effects Modeling
ABSTRACT Modafinil is being used as a novel wake-promoting psychostimulant. To develop rational dosing schemes, given that China has 56 ethnicities that may have various response to modafinil, it is essential to characterize the population pharmacokinetics of modafinil in some selected ethnicities. One- and two-compartment models were used to fit the plasma concentration time data of 49 Chinese healthy volunteers, including the ethnicities of Han, Mongolian, Korean, Uygur, and Hui, using the nonlinear mixed-effects modeling approach. The data were best described using a two-compartment model with linear elimination. The influences of ethnicity, sex, height, body weight, and body mass index on modafinil pharmacokinetic parameters were investigated. The estimated population parameters of modafinil were as follows: clearance of central compartment was 3.51 L/h and clearance of intercompartment was 7.41 L/h; the volume of the central compartment was 3.85 L and the volume of the peripheral compartment was 45.8 L. The interindividual variability in clearance of central compartment and clearance of intercompartment were 23.2% and 22.1%, and in volume of the central compartment and volume of the peripheral compartment were 90.9% and 16.6%, respectively. A population pharmacokinetic model was established and validated, which adequately described the population pharmacokinetics of modafinil in Chinese healthy volunteers. The results indicated that sex has a significant effect on the metabolism of modafinil, whereas ethnicity has a significant effect on the volume of the central compartment. A good fit was achieved from the population pharmacokinetic analysis that could assist in establishing appropriate modafinil dose regimens.
- [Show abstract] [Hide abstract]
ABSTRACT: Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics (γ-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks, developing suitable toxicological analysis procedures, and finally for interpretating drug testing results.Pharmacogenomics 02/2011; 12(2):215-33. DOI:10.2217/pgs.10.171 · 3.43 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Modafinil is a psychostimulant used to treat excessive sleepiness. The aim of this study was to develop a population pharmacokinetic model of modafinil and its major metabolites in Chinese male adults and to identify covariates that predict variability in disposition. Eighty healthy volunteer subjects were randomized to 4 oral dose groups: 3 doses of 50 mg of modafinil, 3 doses of 100 mg of modafinil, 2 doses of 200 mg of modafinil plus 1 dose of placebo, or 3 doses of placebo (each dose given 8 hourly). Blood samples were collected up to 58 hours post-first dose for plasma concentrations of modafinil and its metabolites. Pharmacokinetic data analyses were performed using noncompartmental and compartmental approaches. The population pharmacokinetic study was conducted using the nonlinear mixed-effects model software, NONMEM, and validated using the bootstrap, crossvalidation and visual predictive check approaches. Data were best described by a 5-compartment model: 2 compartments for modafinil (first-order absorption from gut compartment) and 1 each for modafinil acid and modafinil sulfone. A covariate analysis identified body weight as influencing volumes of the central and peripheral compartments for modafinil. All the parameters were estimated with good precision (relative standard error < 39%). The visual predictive check found that the final pharmacokinetic model adequately predicted observed concentrations of all 3 molecular species. The authors developed dosing schedules to achieve minimum trough plasma modafinil concentrations of 3 mcg/mL. A robust population pharmacokinetic model for modafinil and its metabolites was developed for the first time. Based on this model, individualized dosing based on weight is now possible.Therapeutic drug monitoring 12/2011; 33(6):719-29. DOI:10.1097/FTD.0b013e318237a9e9 · 1.93 Impact Factor
- [Show abstract] [Hide abstract]
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.Acta Pharmacologica Sinica 10/2012; 33(11). DOI:10.1038/aps.2012.124 · 2.50 Impact Factor