Department of Medical Oncology, Erasmus MC Cancer Institute, Josephine Nefkens Building, Room Be-424, PO Box 5201, 3008 AE, Rotterdam, The Netherlands.
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
Clin Pharmacokinet. 2019 May;58(5):651-658. doi: 10.1007/s40262-018-0719-5.
As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations.
The decreased function alleles CYP3A4 15389 C > T (*22), ABCB1 3435 C >T, ABCG2 421 C >A, and ABCG2 34G >A were analyzed within a recently developed population-pharmacokinetic model.
Incorporation of CYP3A422 in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: - 9.7; p < 0.005). Simulated median trough concentrations of cancer patients with CYP3A422 with 600 mg once daily or 800 mg once daily were 31 and 35 mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600 mg once daily or 800 mg once daily were 18 and 20 mg/L, respectively.
This analysis shows that CYP3A422 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A422 status could be considered.
帕唑帕尼的血药谷浓度与治疗结果相关，因此我们探讨了帕唑帕尼消除途径中的单核苷酸多态性是否会影响系统帕唑帕尼浓度。
在最近开发的群体药代动力学模型中分析了 CYP3A4 15389 C>T (*22)、ABCB1 3435 C>T、ABCG2 421 C>A 和 ABCG2 34G>A 的功能降低等位基因。
将 CYP3A422 纳入模型后，变异携带者的清除率降低了 35%（0.18 比 0.27 L/h；目标函数值差异：-9.7；p<0.005）。携带 CYP3A422 的癌症患者每日接受 600 mg 或 800 mg 一次的模拟中位谷浓度分别为 31 和 35 mg/L。每日接受 600 mg 或 800 mg 一次的 CYP3A4*22 携带者以外人群的模拟谷浓度分别为 18 和 20 mg/L。
该分析表明 CYP3A422 杂合子的帕唑帕尼清除率显著降低，因此可考虑根据 CYP3A422 状态调整剂量。
