Tan Zhiyuan, Völler Swantje, Yin Anyue, Rieborn Amy, Gelderblom Hans, van der Hulle Tom, Knibbe Catherijne A J, Moes Dirk Jan A R
Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Clin Pharmacokinet. 2025 May;64(5):715-728. doi: 10.1007/s40262-025-01504-5. Epub 2025 Apr 22.
Pazopanib is approved for metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma (STS) in a dose of 800 mg once daily (QD) taken under fasted conditions. In clinical practice, approximately 60% of patients require dose reductions due to toxicity, with severe liver toxicity necessitating treatment interruptions in over 10% of cases. While a trough concentration (C) target of ≥ 20.5 mg/L has been established for mRCC efficacy, no specific threshold exists for liver toxicity. The objectives of this study were to develop a population pharmacokinetic (POPPK), an exposure-liver toxicity, and an exposure-tumor size dynamics model to optimize pazopanib initial dose in real-world patients.
In total, 135 patients were included and treated with a median starting dose of 800 mg (interquartile range, IQR: 600-800 mg) QD pazopanib fasted with a median follow-up of 120 (IQR 63-372) days. A population pharmacokinetic model was developed using 460 concentration measurements from 135 patients. Exposure-liver toxicity was evaluated using time-to-event modeling, and exposure-tumor size dynamics was evaluated using tumor growth modelling.
The liver toxicity model, with 27 cases of grade ≥ 2 liver toxicity out of 135 patients (20%), identified a C threshold of > 34 mg/L associated with a 3.35-fold increased toxicity risk (P < 0.01). Model simulations showed that an initial dose of 600 mg QD significantly reduced liver toxicity risk (P < 0.001) while maintaining C ≥ 20.5 mg/L for 76% of the simulated individuals. Tumor size dynamics were analyzed using baseline and posttreatment tumor size measurements from 111 patients. The introduction of primary resistance by using a mixture model improved the model fit significantly. Tumor growth and decay rates differed between mRCC and STS but showed no pazopanib exposure dependency across the studied range, suggesting maximal tumor inhibition at current exposure levels.
These findings suggest that an initial pazopanib dose of 600 mg fasted, followed by model-informed precision dosing to maintain C between 20 and 34 mg/L, may improve efficacy-toxicity balance and mitigate treatment interruptions.
帕唑帕尼被批准用于治疗转移性肾细胞癌（mRCC）和软组织肉瘤（STS），剂量为每日一次800mg（QD），需在空腹条件下服用。在临床实践中，约60%的患者因毒性需要降低剂量，超过10%的病例因严重肝毒性需要中断治疗。虽然已确定mRCC疗效的谷浓度（C）目标≥20.5mg/L，但对于肝毒性尚无特定阈值。本研究的目的是建立群体药代动力学（POPPK）模型、暴露-肝毒性模型和暴露-肿瘤大小动态模型，以优化现实世界患者的帕唑帕尼初始剂量。
共纳入135例患者，接受帕唑帕尼每日一次800mg（四分位间距，IQR：600 - 800mg）的中位起始剂量空腹治疗，中位随访时间为120（IQR 63 - 372）天。利用135例患者的460次浓度测量数据建立群体药代动力学模型。采用事件发生时间模型评估暴露-肝毒性，采用肿瘤生长模型评估暴露-肿瘤大小动态变化。
在135例患者中有27例（20%）发生≥2级肝毒性，肝毒性模型确定C阈值>34mg/L时，毒性风险增加3.35倍（P < 0.01）。模型模拟显示，初始剂量600mg QD可显著降低肝毒性风险（P < 0.001），同时76%的模拟个体维持C≥20.5mg/L。利用111例患者的基线和治疗后肿瘤大小测量数据分析肿瘤大小动态变化。采用混合模型引入原发性耐药显著改善了模型拟合。mRCC和STS的肿瘤生长和消退率不同，但在所研究范围内未显示出帕唑帕尼暴露依赖性，表明在当前暴露水平下肿瘤抑制达到最大程度。
这些研究结果表明，初始空腹服用帕唑帕尼剂量600mg，随后根据模型指导进行精准给药以维持C在20至34mg/L之间，可能会改善疗效-毒性平衡并减少治疗中断。
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