<p><b>OBJECTIVE</b>To evaluate the effect of covariates on the pharmacokinetic profiles of naringin in the total flavonoids of Drynaria fortunei (Kunze) J. Sm. in the Qianggu Capsule () by evaluating Chinese women with primary osteoporosis.</p><p><b>METHODS</b>A total of 98 female patients from the communities of Jingshan, Beixinqiao, Jiaodaokou, Chaoyangmen, and Donghuamen in Beijing, China, aged 40 to 80 years, were included in this study. Blood samples were collected before and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after a single oral dose of Qianggu Capsule. The concentration in blood samples from 32 patients before and 0.5, 1, 2, 3, and 4 h after drug administration were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and full set of pharmacokinetic data was analyzed with nonlinear mixed-effect modeling (NONMEM) software. The mean of population parameters clearance (C1), central distribution volume (V), absorption rate constant (Ka1), inter-compartmental clearance (C2), peripheral distribution volume (V2) were set as parameters and estimated through base model, covariate model, and final model. Age, height, weight, blood urea nitrogen (BUN), serum creatinine (Scr), alanine transaminase (ALT), aspartate transaminase (AST), hyperlipidemia, Liver (Gan) Kidney (Shen) yin insufficiency (GSYI), Kidney (Shen) yang insufficiency (SYI) were set as covariates.</p><p><b>RESULTS</b>The relationships between these parameters and covariates were analyzed. The results showed that C1 was the main parameter influenced by the selected covariates among the population parameters, and the relationships between the covariates and C1 were analyzed, among the selected covariates hyperlipidemia was identified as significant covariate of C1.</p><p><b>CONCLUSION</b>The pharmacokinetic behaviors of naringin are altered with hyperlipidemia in Chinese women with primary osteoporosis.</p>