Population Pharmacokinetics of Anlotinib, a Multiple Receptor Tyrosine Kinase Inhibitor, in Chinese Patients With Malignant Tumors

Abstract The objective of this study was to investigate the pharmacokinetic behavior of anlotinib in Chinese patients with malignant tumors using the population approach. 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. A population pharmacokinetic model was established using nonlinear mixed‐effects model method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetics was investigated in a covariate analysis. The final model was evaluated using goodness‐of‐fit plots, visual predictive check, and bootstrap methods. The pharmacokinetic profile of anlotinib was best described by a 1‐compartment model with first‐order absorption and first‐order elimination. The population estimates of the apparent total clearance, apparent volume of distribution, and absorption rate constant were 8.91 L/h, 1950 L, and 0.745/h, respectively. Body weight was identified as a significant covariate on apparent volume of distribution. 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 based on the simulations of the individual body weight effects. Taken together, this population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors and supports the same starting dose among them.