Individualized pazopanib dosing: A prospective feasibility study in cancer patients

Purpose: 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 (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically guided individualized dosing. Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was <grade 3. Results: In total, 17 patients had at least one Cmin <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. Cmin 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 Cmin levels ≥ 20.0 mg/L. Of these, 9 patients with a high Cmin 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, Cmin remained above the threshold at 28.2 mg/L (25.3%). Conclusions: 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.