Relation between Plasma Trough Concentration of Pazopanib and Progression-Free Survival in Metastatic Soft Tissue Sarcoma Patients

Abstract

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.

Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review

“…41 Noda et al 8 also suggested a therapeutic concentration range of 20.5–50.3 mcg/mL in patients with RCC. Recently, Minot-This et al 47 confirmed a target C trough > 27 mcg/mL in a large cohort of patients with STS ( N = 95). This recommendation was based on the finding that a longer OS was observed in patients with C trough > 27 mcg/mL on day 15 compared with patients with C trough between 12.0 and 27 mcg/mL.…”

“…41 Noda et al 8 also suggested a therapeutic concentration range of 20.5-50.3 mcg/mL in patients with RCC. Recently, Minot-This et al 47 confirmed a target C trough . 27 mcg/mL in a large cohort of patients with STS (N = 95).…”

“…Moreover, a significant difference between the groups below and above the target (defined as 20.5 mcg/mL and 27.5 mcg/mL, respectively) in some of the end points was reported in 2 other studies (comprising 130 out of 768 patients). 41,47 In the remaining 4 studies, including the 26 patients with STS from the study of Verheijen et al 41 (thus comprising the remaining 125 out of 768 patients), no difference in treatment outcomes was observed between the groups that were below and above the target C trough . 8,[48][49][50] The level of significance in these studies was not reached, probably due to the low number of participants with distinct C trough values, as reported in the study by Noda et al 8 (n = 3, 11, and 13 in the C trough groups ,20.5 mcg/mL, 20.5-50.3 mcg/mL, and .50.3 mcg/mL, respectively).…”

“…Overall, out of 8 studies that investigated toxicity with respect to drug exposure, 6 studies confirmed such an indirect relationship (676 out of 777 patients in total). 8,16,38,40,46,47 In the 2 studies in which a relationship was not found, 101 patients were enrolled. 41,49 Of these 2 studies, one was retrospective.…”

“…64,67 However, LC-MS/MS equipment can be expensive to maintain and may require highly skilled operators. Alternatively, some authors 8,9,47,49 reported using LC-UV methods for pazopanib level determination, which are less expensive and more accessible than LC-MS/MS. Interestingly, Dziadosz et al 68 achieved an LOQ of 20 ng/mL using LC-UV with ;50% sample recovery, outperforming many LC-MS approaches.…”