Abstract 1291: A phase 1 open-label single-radiolabeled dose study of PF299804 in healthy male volunteers
Authors: Bello Carlo L. , Smith Evan , Ruiz Ana , Ni Grace , McCormick Carol , Alvey Christine , Loi Cho-Ming 
Published: June 2012

Objectives: To characterize the primary routes of elimination of the second-generation, oral, irreversible, pan-HER tyrosine kinase inhibitor, PF299804; to evaluate the pharmacokinetics (PK) of total radioactivity and of PF299804; and to identify the metabolites of PF299804 in plasma, urine, and feces in healthy volunteers (HVs).

Methods: This Phase 1 study evaluated the mass balance and PK of PF299804 in HVs (18-55 yrs), following a single 45-mg oral dose containing ∼100 µCi [14C] PF299804. Serial samples were collected over an 18-day period. Radioactivity measurements of blood, plasma, urine, and feces were conducted by liquid scintillation spectroscopy. Plasma samples were analyzed for PF299804 and the metabolite PF5199265 using high-performance liquid chromatography with atmospheric pressure ionization tandem mass spectrometry. Plasma, urine, and fecal samples were analyzed for metabolic profiling of PF299804; major metabolites of PF299804 were identified where possible.

Results: 6 HVs (male; median age 31.5 yrs) received treatment and were evaluated for PK and safety. 78.8% of the radiolabeled material was excreted in feces, and a further 3.2% was recovered in urine. Peak concentrations of PF299804 in plasma generally occurred 12 hrs after oral dosing, and 6 hrs post-dose for PF5199265. Plasma exposure for the metabolite was approximately one-third of that for the parent compound. Terminal plasma half-life (t1/2) averaged about 55 hrs for PF299804 and 73 hrs for PF5199265. Peak concentrations of total radioactivity in plasma occurred at 12 hrs. Geometric mean Cmax was approximately 2-fold higher and total exposure (AUCinf) was almost 6-fold higher for total radioactivity than for PF299804 in plasma. t1/2 for plasma radioactivity was 182 hrs. PF299804 and its O-desmethyl metabolite, PF5199265, were the major drug-related components in plasma. Other trace components were observed in the profile. The most abundant drug-related components identified in excreta were proposed to be PF299804, PF5199265, a cysteine conjugate (M2), and a mono-oxygenated metabolite (M7). There were no serious adverse events (AEs), severe AEs, or deaths during the study. Mild AEs were reported in 2 HVs: dermatitis acneiform, dizziness, insomnia, and photophobia (all considered related to study drug).

Conclusions: Following single-dose administration of [14C] PF299804 the radiolabeled material was primarily eliminated in feces (78.8%) and, to a lesser degree, in urine (3.2%). Estimates of exposure for total radioactivity in plasma (Cmax and AUCinf) were 2- and 6-fold higher, respectively, than exposure for plasma PF299804, indicating the presence of circulating metabolic product(s). The metabolic profiles indicated that [14C] PF299804 underwent oxidative and conjugative metabolism in HVs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1291. doi:10.1158/1538-7445.AM2011-1291