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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.