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Cancer Chemother Pharmacol. 2013 Aug;72(2):379-85. doi: 10.1007/s00280-013-2207-9. Epub 2013 Jun 13.

A phase I, open-label, mass balance study of [(14)C] dacomitinib (PF-00299804) in healthy male volunteers.

Author information

  • 1Oncology, Pfizer Inc., 235 E. 42nd St, New York, NY 10011, USA. carlo.bello@pfizer.com

Abstract

PURPOSE:

This study aimed to characterize the primary routes of elimination of the pan-HER tyrosine kinase inhibitor, dacomitinib (PF-00299804), to evaluate the pharmacokinetics of total radioactivity and of dacomitinib and to identify the metabolites of dacomitinib in plasma, urine, and feces in the healthy volunteers.

METHODS:

Six male healthy volunteers (mean age 31.5 years) received a single 45-mg oral dose containing ~100 μCi [(14)C] dacomitinib. Whole blood, urine, and fecal samples were collected throughout the study and analyzed for total radioactivity by liquid scintillation counting. Safety evaluations included vital signs, 12-lead ECGs, safety laboratory tests, and monitoring of adverse events.

RESULTS:

78.8 % of the radiolabeled material was excreted in feces, and 3.2 % was recovered in urine. Peak concentrations of dacomitinib in plasma occurred 12 h (median) after oral dosing. Mean terminal plasma half-life was 55 and 182 h for dacomitinib and total plasma radioactivity, respectively. Geometric mean C max was approximately 2-fold higher, and total exposure (AUCinf) was almost 6-fold higher for total radioactivity than for dacomitinib in plasma. O-desmethyl dacomitinib (PF-05199265) was the major circulating metabolite. T max of this metabolite occurred 6 h after oral dosing with dacomitinib. Plasma exposure for the metabolite was one-third that of the parent compound. There were no serious/severe adverse events or deaths during the study. Dacomitinib was well tolerated.

CONCLUSIONS:

In humans, [(14)C] dacomitinib underwent oxidative and conjugative metabolism. Most of the administered dose was eliminated via the fecal route, and the major circulating metabolite was PF-05199265.

PMID:
23760812
[PubMed - indexed for MEDLINE]
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