RPT835 (recommended INN, alofanib) is a novel allosteric FGFR2 inhibitor with activity in FGFR2-expressing women's cancers. Administration of RPT835 intravenously (iv) daily demonstrated dramatic effect in ovarian cancer xenografts compared with RPT835 orally daily [S. Tjulandin et al. AACR 2015]. Here we explore the pharmacokinetic (PK) profile of RPT835.
Three preclinical PK studies were conducted. In Study 1, RPT835 was administered to 49 male BALB/C mice via two routes (oral and iv). Mice in group 1 received a single iv injection of the RPT835 (30 mg/kg), while mice in group 2 received a single dose of RPT835 (30 mg/kg) via oral gavage. The aim of the Study 2 was to evaluate the PK for RPT835 in 24 male Sprague Dawley rats after a single iv dose of 22 mg/kg and oral dosing in capsules at three dose levels (22, 110 and 220 mg/kg). In Study 3, PK of pharmaceutical form of RPT835 in male Sprague Dawley rats after a single iv dose of 55.3, 113.8 and 218.7 mg/kg was evaluated. Six animals per dose group were dosed, with plasma samples collected from the tail vein up to 24 hours. Plasma concentrations were quantified by LC-MS/MS using a research qualified method. The PK data are summarized in Table.
Following oral administration, RPT835 appeared rapidly in plasma (within 30 min), but could not be detected after 2 hours. Bioavailability for oral administration could not be calculated but is estimated to be low (<1%). Following single iv bolus dosing of RPT835, animals showed a moderate intra-individual variability in plasma levels. RPT835 plasma levels were quantifiable up to 8 hours post dose in all animals in Study 3. The compound resulted in a moderate and low clearance (32-12% of liver blood flow), small volume of distribution (0.26-0.5 L/kg) and short half-life (0.4-0.9 h). Based on results of PK, protocol of Phase IB study of continuous iv infusion of RPT835 via pump in patients with ovarian cancer was developed at the ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research (“Flims17”).
|Study||Group (dose, mg/kg)||C0/Cmax, ng/ml||Tmax, h||t1/2||AUC, h*ng/mL||CL, mL/min/kg||Vss, L/kg||F, %|
|1||iv, 30||57739||-||0.93||5803||86.7||6.9||NC - Parameter cannot be calculated|
Citation Format: Ilya Tsimafeyeu, Mikhail Byakhov, Vlatka Bencetić Mihaljević, Jasna Padovan, Genoveva Murillo, Sergei Tjulandin. Preclinical pharmacokinetic studies of RPT835, an allosteric FGFR2 inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B146.
- ©2015 American Association for Cancer Research.