Format

Send to

Choose Destination
Clin Pharmacokinet. 2017 Sep;56(9):987-997. doi: 10.1007/s40262-017-0510-z.

Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib: Towards Optimized Dosing.

Author information

1
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. r.verheijen@nki.nl.
2
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
3
Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
4
Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
5
Department of Clinical Pharmacy, Utrecht University Medical Center, Utrecht, The Netherlands.

Abstract

Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.

KEYWORDS:

Advanced Solid Tumor; Pazopanib; Renal Cell Carcinoma; Renal Cell Carcinoma Patient; Sunitinib

PMID:
28185218
PMCID:
PMC5563343
DOI:
10.1007/s40262-017-0510-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center