Article

Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species

Authors: Chen-chun ZHONG1,2, Feng CHEN1, Jun-ling YANG1, Wei-wei JIA1, Li LI1, Chen CHENG1, Fei-fei DU1, Su-ping ZHANG1, Chengying XIE1, Na-ting ZHANG1, Olajide E OLALEYE1, Feng-qing WANG1, Fang XU1, Li-guang LOU1, Dong-ying CHEN1, Wei NIU1, Chuan LI1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Shanghai 201203, China
Corresponding to: Wei NIU: niuwei@simm.ac.cn, Chuan LI: chli@simm.ac.cn,
DOI: 10.1038/aps.2017.199
Received: 24 April 2017
Accepted: 19 December 2017
Advance online: 5 April 2018

Abstract

Abstract
Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%–58% in rats and 41%–77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h–1·kg–1; dogs, 0.40±0.06 L·h–1·kg–1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 μmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.
Keywords: anlotinib; tyrosine kinase inhibitor; absorption; distribution; metabolism; excretion; pharmacokinetics

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