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”).

PK results 
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, % 
iv, 30 57739 0.93 5803 86.7 6.9 NC - Parameter cannot be calculated 
 oral/gavage, 30 43.6 1-2 NC NC NC NC NC 
iv, 22 79323 0.44 14234 27.1 0.47 
 oral/caps, 22 22.0 2.0 NC 68.0 0.36 
 oral/caps, 110 82.3 2.5 NC 1.0 0.18 
 oral/caps, 220 110.0 1.0 NC 1.0 0.18 
iv, 55.3 246499 0.86 37105 23.8 0.3 
 iv, 113.8 432342 0.73 130788 14.8 0.29 
 iv, 218.7 730496 0.68 363145 10.1 0.26 
PK results 
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, % 
iv, 30 57739 0.93 5803 86.7 6.9 NC - Parameter cannot be calculated 
 oral/gavage, 30 43.6 1-2 NC NC NC NC NC 
iv, 22 79323 0.44 14234 27.1 0.47 
 oral/caps, 22 22.0 2.0 NC 68.0 0.36 
 oral/caps, 110 82.3 2.5 NC 1.0 0.18 
 oral/caps, 220 110.0 1.0 NC 1.0 0.18 
iv, 55.3 246499 0.86 37105 23.8 0.3 
 iv, 113.8 432342 0.73 130788 14.8 0.29 
 iv, 218.7 730496 0.68 363145 10.1 0.26 

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.