Pharmacy department IUCT (Institut Universitaire du Cancer) Oncopole, Institut Claudius Regaud, 1 avenue Irène Joliot-Curie, Toulouse CEDEX 9, 31059, France.
Oncology department IUCT (Institut Universitaire du Cancer) Oncopole, Institut Claudius Regaud, 1 avenue Irène Joliot-Curie, Toulouse CEDEX 9, 31059, France.
Eur J Clin Pharmacol. 2020 Apr;76(4):579-587. doi: 10.1007/s00228-020-02828-w. Epub 2020 Jan 13.
Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life.
This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity.
Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors).
P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.
舒尼替尼和帕唑帕尼是两种酪氨酸激酶抑制剂（TKI），可能是潜在的药代动力学药物相互作用（P-PK-DDI）的靶点。虽然强细胞色素 P4503A（CYP3A4）抑制剂或诱导剂可能会导致血浆 TKI 浓度发生临床相关的改变，但弱抑制剂的作用尚不清楚。本研究的目的是评估弱 P-PK-DDI 与真实生活中临床相关毒性之间的关联。
这是一项单中心回顾性研究，纳入了接受舒尼替尼或帕唑帕尼治疗的任何恶性肿瘤患者，这些患者在开始 TKI 治疗前进行了 PK-DDI 分析。主要终点是 P-PK-DDI 与治疗 1 个月后剂量减少之间的相关性。次要终点是 PK-DDI 与因毒性而停药之间的相关性。
评估了 76 例患者。在 14 例患者中发现了弱 CYP3A4 或 P-糖蛋白抑制的 P-PK-DDI。在有或没有 P-PK-DDI 的患者中，第 1 个月的剂量分别减少了 57.1%和 17.7%（p=0.003），药物分别停用了 42.8%和 11.3%（p=0.011）。多变量分析发现，P-PK-DDI（CYP3A4 和 P-糖蛋白抑制剂）与剂量减少，以及药物停药与 PK-DDI（CYP3A4 抑制剂）之间存在显著相关性。
P-PK-DDI 与剂量减少和因毒性而停药有关。需要评估这种关系的因果关系；因此，TKI 治疗的患者需要进行治疗药物监测。
