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Population pharmacokinetics and covariate analysis of anlotinib in patients with malignant tumors
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  • Gaoqi Xu,
  • Dihong Yang,
  • Junfeng Zhu,
  • Haiying Ding,
  • Wenxiu Xin,
  • Like Zhong,
  • Liqin Zhu,
  • Luo Fang
Gaoqi Xu
Zhejiang Cancer Hospital

Corresponding Author:[email protected]

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Dihong Yang
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Junfeng Zhu
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Haiying Ding
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Wenxiu Xin
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Like Zhong
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Liqin Zhu
Tianjin First Central Hospital
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Abstract

Aims Anlotinib is a novel oral tyrosine kinase inhibitor that targets VEGFR-2, VEGFR -3, FGFR1-4, PDGFR-α, PDGFR-β, c-Kit, and Ret. This study aimed to develop a population pharmacokinetic model of anlotinib in patients with malignant tumors and identify various covariates that might affect its pharmacokinetic parameters. Methods 407 plasma concentrations from 16 patients were analyzed to establish a population pharmacokinetic model using the nonlinear mixed-effects model method. All patients were administered anlotinib (12 mg) orally, as a single drug therapy. The potential influence of demographic, hepatic, and renal function data was investigated using automated stepwise covariate model. The final model was evaluated using diagnostic goodness-of-fit plots, bootstrap, and visual predictive check methods. Results A one-compartment model with first-order absorption and elimination adequately described anlotinib pharmacokinetics. The population estimates of apparent total plasma clearance (CL/F) was 9.26 L/h (29.20% IIV), apparent volume of distribution (V/F) was 2010 L (29.20 IIV), and absorption rate constant (Ka) was 0.64 h-1 (56.70% IIV). Total cholesterol (TC) was identified as a covariate affecting CL/F, while alkaline phosphatase (ALP) was found to be statistically significant for V/F. Conclusion The population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors. TC and ALP might have a slight effect on the pharmacokinetic profile of anlotinib.