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 [(14)C]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 [(14)C]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%.

Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity

“…The disparity between expression level and metabolic activity of CYP3A4 could be due to its functional regulation at post-trascriptional level3940. Notwithstanding these differences, we anticipate that HLCs from all five patient-specific iPSC lines will be capable of metabolizing PZ as CYP3A4 and CYP1A2 activities primarily mediate metabolism of PZ30.…”

“…PZ belongs to the class of tyrosine kinase inhibitor drugs, several among which are known to be metabolized to reactive intermediates partially accounting for their toxicity profiles29. However, for PZ no reactive metabolites have been identified in patients30, and pharmacogenetic analyses have yielded weak associations with two genetic markers HFE 31 and UGT1A1 32 for elevated ALT and bilirubin levels, respectively. The high incidence of hepatotoxicity, the obscure mechanism underlying this and the paucity of biomarkers for predicting hepatotoxicity, prompted the choice of PZ as the drug to demonstrate the utility of patient-specific HLCs for modeling idiosyncratic hepatotoxicity.…”

Determination of unbound fraction of pazopanib in vitro and in cancer patients reveals albumin as the main binding site

“…Pazopanib as monotherapy given orally at 800 mg once daily is approved for the treatment of advanced renal cell carcinoma, soft tissue sarcoma and currently under investigation in multiple tumour types [2][3][4][5][6]. Pazopanib exhibits high inter-individual variability mainly due to its pharmacokinetic properties: low bioavailability (ranging from 14 to 39 % [7]), oxidative metabolism by CYP3A4 and substrate of P-glycoprotein and Breast Cancer Resistance Protein. Several studies have demonstrated pharmacokinetic/pharmacodynamic (PK/PD) relationships, suggesting that therapeutic drug monitoring (TDM) of pazopanib would be useful for individualized dosing of this drug [1,[8][9][10].…”

Molecular‐targeted therapy in advanced renal cell carcinoma based on pharmacokinetics, pharmacodynamics and pharmacogenetics: A proposed strategy

“…Pazopanib is another multikinase inhibitor that provides both therapeutic effect and favorable tolerability . It is metabolized mainly by CYP3A4, with CYP1A2 and CYP2C8 contributing to a smaller extent, to form its metabolites (M1–M7) . Only the M2 (GSK1268997) metabolite has a bioactivity similar to pazopanib.…”