Metabolism, excretion and pharmacokinetics of [¹⁴C]glasdegib (PF-04449913) in healthy volunteers following oral administration

Abstract

1. The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100 mg/100 μCi [¹⁴C]glasdegib to six healthy male volunteers (NCT02110342).

2. The peak concentrations of glasdegib (890.3 ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75 hours post-dose. The AUC_inf were 8469 ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity.

3. Mean recovery of [¹⁴C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0–120 hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites.

4. Elimination of [¹⁴C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.

Keywords:

• ADME
• Glasdegib
• mass balance, PF-04449913
• smoothened inhibitor

Acknowledgements

The authors thank Doctors Deepak Dalvie and Cho-Ming Loi for their scientific guidance and support. In addition, we thank personnel from Covance Laboratories Inc. (Madison, WI and Indianapolis, IN, USA) for radioanalysis support of the human ADME study and for quantitation of glasdegib in human plasma and urine samples; Angus Nedderman at Unilabs (Sandwich, UK) for metabolite identification support; Kate Ginman for facilitating clinical study conduct; and Klaas Schildknegt for facilitating synthesis of radiolabeled glasdegib. The support of these colleagues is gratefully acknowledged.

Declaration of interests

This study was supported by Pfizer Inc. Doctors. J. L. Lam, A. Vaz, B. Hee, Y. Liang, X. Yang and M. N. Shaik were full-time employees of Pfizer Inc. during the conduct of this study. Medical writing and editorial support was provided by S. Mariani, MD, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc.