Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer

Abstract

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma.

2. In this two-part study, we investigated the metabolism, disposition of [¹⁴C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer.

3. In part A, three men each received a single oral dose of [¹⁴C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose).

4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5–28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.

Keywords::

• Pazopanib
• human
• absorption
• bioavailability
• pharmacokinetics
• metabolism
• excretion

Acknowledgements

We acknowledge Dr. Ken Lawrie for the synthesis and purification of [¹⁴C]pazopanib; Ms. Trudy Luce for assisting in pharmacokinetic analysis; Dr. Angela Bickford, Dr. Christopher Carpenter, Mr. Ernest Schubert, Dr. Konstantine Skordos and Dr. Stephen Castellino for reviewing the manuscript.

Declaration of interest: The authors report no conflict of interest. This work was supported by GlaxoSmithKline. All authors are employees of GlaxoSmithKline and responsible for the writing and content of the paper.