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Clin Cancer Res. 2016 Dec 1;22(23):5738-5746. Epub 2016 Jul 28.

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

Author information

1
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands. r.verheijen@nki.nl.
2
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
3
Department of Medical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.
4
Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
5
Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
6
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.

Abstract

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. 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.

Comment in

PMID:
27470967
DOI:
10.1158/1078-0432.CCR-16-1255
[Indexed for MEDLINE]
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