Individualized Pazopanib Dosing: A Prospective Feasibility Study in Cancer Patients.

Abstract

Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (C_min). Therefore, patients with low C_min might benefit from pharmacokinetically guided individualized dosing. We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib C_min was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured C_min was <20 mg/L and toxicity was <grade 3. In total, 17 patients had at least one C_min <20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. C_min in these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all C_min levels ≥20.0 mg/L. Of these, 9 patients with a high C_min of 51.3 mg/L (45.1%) experienced ≥grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, C_min remained above the threshold at 28.2 mg/L (25.3%). A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738-46. ©2016 AACRSee related commentary by Ornstein and Rini, p. 5626.