Minot-This Marie-Sophie, Boudou-Rouquette Pascaline, Jouinot Anne, de Percin Sixtine, Balakirouchenane David, Khoudour Nihel, Tlemsani Camille, Chauvin Jonathan, Thomas-Schoemann Audrey, Goldwasser François, Blanchet Benoit, Alexandre Jérôme
Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Medical Oncology, ARIANE, Cochin Hospital, 75014 Paris, France.
INSERM U-1016, CNRS UMR-8104, University of Paris, Institut Cochin, 75014 Paris, France.
Pharmaceutics. 2022 Jun 9;14(6):1224. doi: 10.3390/pharmaceutics14061224.
Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor approved to treat soft tissue sarcoma (STS) but associated with a large interpatient pharmacokinetic (PK) variability and narrow therapeutic index. We aimed to define the specific threshold of PAZ trough concentration (Cmin) associated with better progression-free survival (PFS) in STS patients. Methods: In this observational study, PAZ Cmin was monitored over the treatment course. For the primary endpoint, the 3-month PFS in STS was analyzed with logistic regression. Second, we performed exposure−overall survival (OS) (Cox model plus Kaplan−Meier analysis/log-rank test) and exposure−toxicity analyses. Results: Ninety-five STS patients were eligible for pharmacokinetic/pharmacodynamic (PK/PD) assessment. In the multivariable analysis, PAZ Cmin < 27 mg/L was independently associated with a risk of progression at 3 months (odds ratio (OR) 4.21, 95% confidence interval (CI) (1.47−12.12), p = 0.008). A higher average of PAZ Cmin over the first 3 months was associated with a higher risk of grade 3−4 toxicities according to the NCI-CTCAE version 5.0 (OR 1.07 per 1 mg/L increase, CI95 (1.02−1.13), p = 0.007). Conclusion: PAZ Cmin ≥ 27 mg/L was independently associated with improved 3-month PFS in STS patients. Pharmacokinetically-guided dosing could be helpful to optimize the clinical management of STS patients in daily clinical practice.
帕唑帕尼（PAZ）是一种口服血管生成抑制剂，已被批准用于治疗软组织肉瘤（STS），但患者间药代动力学（PK）变异性大且治疗指数窄。我们旨在确定与STS患者更好的无进展生存期（PFS）相关的PAZ谷浓度（Cmin）的特定阈值。方法：在这项观察性研究中，在整个治疗过程中监测PAZ Cmin。对于主要终点，采用逻辑回归分析STS患者的3个月PFS。其次，我们进行了暴露-总生存期（OS）（Cox模型加Kaplan-Meier分析/对数秩检验）和暴露-毒性分析。结果：95例STS患者符合药代动力学/药效学（PK/PD）评估标准。在多变量分析中，PAZ Cmin < 27 mg/L与3个月时的进展风险独立相关（优势比（OR）4.21，95%置信区间（CI）（1.47-12.12），p = 0.008）。根据美国国立癌症研究所不良事件通用术语标准第5.0版，前3个月PAZ Cmin的平均水平越高，3-4级毒性的风险越高（每增加1 mg/L，OR为1.07，CI95（1.02-1.13），p = 0.007）。结论：PAZ Cmin≥27 mg/L与STS患者3个月PFS的改善独立相关。在日常临床实践中，以药代动力学为指导的给药可能有助于优化STS患者的临床管理。
