Exploring the Association Between Intra-Patient Variability in Trough Concentration of Pazopanib and Clinical Outcomes in Renal Cell Carcinoma and Soft Tissue Sarcoma Patients.

Abstract

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.