Abstract 1291: A phase 1 open-label single-radiolabeled dose study of PF299804 in healthy male volunteers

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL 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][1] 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][1] 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][1]; major metabolites of [PF299804][1] 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][1] 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][1] 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][1] in plasma. t1/2 for plasma radioactivity was 182 hrs. [PF299804][1] 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][1], 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][1] 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][1], indicating the presence of circulating metabolic product(s). The metabolic profiles indicated that [14C] [PF299804][1] 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 [1]: /lookup/external-ref?link_type=GEN&access_num=PF299804&atom=%2Fcanres%2F71%2F8_Supplement%2F1291.atom