Population Pharmacokinetic and Covariate Analysis of Anlotinib in Patients with Malignant Tumors

Abstract Purpose The objective of this study was to develop a population pharmacokinetic (popPK) model of anlotinib and to investigate the impact of various covariates in patients with malignant tumors. Methods A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single-dose phase and 12 mg once daily in the multiple-dose phase. PopPK model was established using nonlinear mixed-effects model (NONMEM) method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetic was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. Results The pharmacokinetic profile of anlotinib was best described by a one-compartment model with first-order absorption and linear elimination. The population estimates of the apparent total clearance (CL/F), apparent volume of distribution (V/F) and absorption rate constant (Ka) were 8.91 L/h, 1950 L and 0.745 h-1, respectively. Body weight was identified as a significant covariate on V/F. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant in the simulations of the individual body weight effects. No obvious bias was found in the final model by bootstrap and VPC methods. Conclusion This popPK model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors. Anlotinib does not need any dose modifications since the effect size for the individual covariate is not considered clinically relevant with anlotinib exposure.