Population Pharmacokinetics and Pharmacogenetics of Apatinib in Adult Cancer Patients
British journal of clinical pharmacology
Apatinib; CYP3A5 genotype; population pharmacokinetics; systemic cancer type
OBJECTIVE: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. CYP3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by HPLC-MS/MS. CYP3A5 genotype was determined by TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, non digestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower CL/F and V /F than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with non digestive system cancer had higher V /F and K than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33% - 50.00% higher than that in CYP3A5*1 expressers. CONCLUSION: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.
Yang, Xin-Mei; Ye, Pan-Pan; Liu, Xiao-Lin; Guo, Zi-Xuan; Kan, Min; Li, Qian; Song, Lin-Lin; Liu, Hong-Ying; Chen, Ke-Guang; Shi, Jin-Yi; Zhang, Ye-Hui; Li, Ya; Zhao, Fu-Rong; van den Anker, John; Li, Yan; and Zhao, Wei, "Population Pharmacokinetics and Pharmacogenetics of Apatinib in Adult Cancer Patients" (2023). GW Authored Works. Paper 2253.