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 PFS and tumor shrinkage appears in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically-guided individualized dosing.
We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At week 3, 5 and 7 the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was < grade 3.
In total, 17 patients had at least one Cmin <20 mg/L at week 3, 5 and 7. Of these, 10 were successfully treated with a pharmacokinetically-guided dose escalation, leading to daily dosages ranging from 1000 to 1800 mg daily. 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 {greater than or equal to}20 mg/L. Of these, nine patients with a high Cmin of 51.3 mg/L (45.1%) experienced {greater than or equal to} 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%).
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 1800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes such as progression free survival.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Jul 28 [Epub ahead of print]
Remy B Verheijen, Sander Bins, Ron H J Mathijssen, Martijn Lolkema, Leni van Doorn, Jan H M Schellens, Jos H Beijnen, Marlies Hg Langenberg, Alwin Dr Huitema, Neeltje Steeghs
Dept. of Pharmacy & Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek ., Dept. Medical Oncology, Erasmus MC Cancer Institute., Medical Oncology, Erasmus MC Cancer Institute., Medical Oncology, ErasmusMC Cancer institute., Medical Oncology, Erasmus University Medical Center., Department of Clinical Pharmacology, Division of Medical Oncology, Netherlands Cancer Institute., Pharmacy and Pharmacology, Netherlands Cancer Institute., Medical Oncology, University Medical Center Utrecht., Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute., Dept of Medical Oncology, The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital.