Rieborn Amy, Giraud Eline L, van Gelder Teun, Gelderblom Hans, van Erp Nielka P, van der Hulle Tom, Moes Dirk Jan A R
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
Clin Pharmacol Ther. 2025 Aug;118(2):489-496. doi: 10.1002/cpt.3728. Epub 2025 Jun 1.
Pazopanib is an oral tyrosine kinase inhibitor used in patients with either metastatic renal cell carcinoma or soft tissue sarcoma. Pazopanib has a high interindividual variability in pharmacokinetics and pharmacodynamics and a well-established exposure-response relationship. Therefore, therapeutic drug monitoring is recommended to improve the efficacy-toxicity balance. Intra-patient variability in pazopanib pharmacokinetics is moderate with a mean of 24.7%. In other fields, such as transplantation medicine, a high intra-patient variability of immunosuppressive drugs has previously been associated with worse outcomes. Whether this also applies to therapeutic modalities in oncology is unknown. The aim of this study was to explore the relationship between pazopanib intra-patient variability and clinical outcomes. Data from patients diagnosed with either metastatic renal cell carcinoma or soft tissue sarcoma treated with pazopanib guided by routine therapeutic drug monitoring with at least three available pazopanib trough concentrations were retrieved. Non-dose corrected estimated trough concentrations were used to calculate intra-patient variability. Among 144 patients, median intra-patient variability was 30.2%. The high intra-patient variability group (intra-patient variability > 30.2%) was at risk for worse progression-free survival (HR 1.42; 95% CI 0.85-2.35) and overall survival (HR 2.17; 95% CI 1.10-4.29) in patients with renal cell carcinoma. No association between a high intra-patient variability and clinical outcomes for patients with soft tissue sarcoma could be established. Our results show that high intra-patient variability is associated with poorer treatment outcomes. A high intra-patient variability urges the treating clinician to address therapy adherence, drug-drug and food-drug interactions, and improve chances for optimal treatment outcome.
帕唑帕尼是一种口服酪氨酸激酶抑制剂，用于治疗转移性肾细胞癌或软组织肉瘤患者。帕唑帕尼在药代动力学和药效学方面存在较高的个体间变异性，且具有明确的暴露-反应关系。因此，建议进行治疗药物监测以改善疗效与毒性之间的平衡。帕唑帕尼药代动力学的患者内变异性适中，平均值为24.7%。在其他领域，如移植医学中，免疫抑制药物的高患者内变异性此前已被认为与较差的预后相关。这是否也适用于肿瘤学的治疗模式尚不清楚。本研究的目的是探讨帕唑帕尼患者内变异性与临床结局之间的关系。检索了在常规治疗药物监测指导下接受帕唑帕尼治疗的转移性肾细胞癌或软组织肉瘤患者的数据，这些患者至少有三次可用的帕唑帕尼谷浓度。使用未校正剂量的估计谷浓度来计算患者内变异性。在144例患者中，患者内变异性的中位数为30.2%。肾细胞癌患者中，高患者内变异性组（患者内变异性>30.2%）无进展生存期（HR 1.42；95%CI 0.85-2.35）和总生存期（HR 2.17；95%CI 1.10-4.29）较差的风险增加。软组织肉瘤患者的高患者内变异性与临床结局之间未发现关联。我们的结果表明，高患者内变异性与较差的治疗结局相关。高患者内变异性促使治疗临床医生关注治疗依从性、药物-药物和食物-药物相互作用，并提高获得最佳治疗结局的机会。
