Abstract B084: Preclinical pharmacokinetic evaluation of alofanib for cancer treatment
Authors: Tsimafeyeu Ilya , Byakhov Mikhail , Bencetić Mihaljević Vlatka , Padovan Jasna , Murillo Genoveva , Dragun Nadezhda , Gavrilova Evgenia , Tjulandin Sergei 
Published: August 2018

Alofanib (RPT835) is a novel allosteric FGFR2 inhibitor with activity in FGFR2-expressing cancers. Here we explore the pharmacokinetic (PK) profile of compound. Five preclinical PK studies were conducted. In Study 1, alofanib 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 alofanib (30 mg/kg), while mice in group 2 received a single dose (30 mg/kg) via oral gavage. The aim of Study 2 was to evaluate the PK 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 alofanib in male Sprague Dawley rats after a single iv dose of 55.3, 113.8 and 218.7 mg/kg was evaluated. Studies 4 and 5 compared PK profile for alofanib in male Sprague Dawley rats after a single intraduodenal (i.d.) and subcutaneous (s.c.) dosing at 29 and 145 mg/kg. 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. StudyGroup(dose, mg/kg)C0/Cmax,ng/mlTmax,ht1/2AUC,h*ng/mLCL,mL/min/kgVss,L/kgF,%1iv, 3057739-0.93580386.76.9NCoral/gavage, 3043.61-2NCNANCNCNC2iv, 2279323-0.441423427.10.47-oral/caps, 2222.02.0NC68.0--0.36oral/caps, 11082.32.5NC1.0--0.18oral/caps, 220110.01.0NC1.0--0.183iv, 55.3246499-0.863710523.80.3-iv, 113.8432342-0.7313078814.80.29-iv, 218.7730496-0.6836314510.10.26-4i.d, 29360.5NC116---i.d, 145980.5NC188---5s.c, 2975130.50.9817218---s.c, 145373000.51.7855020---

NC - Parameter cannot be calculated

Following oral administration, alofanib appeared rapidly in plasma but could not be detected after 2 hours. Bioavailability for oral administration is estimated to be low (&lt;1%). Following single iv bolus dosing, animals showed a moderate intra-individual variability in plasma levels. Alofanib 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). After a single i.d. dose of alofanib, animals showed moderate inter-individual variability in plasma levels, with mean CV of 47 (29 mg/kg) and 69% (145 mg/kg). Alofanib plasma levels were quantifiable up to 8 hours. At a dose of 145 mg/kg, plasma levels were quantifiable up to 24 hours. Following i.d. administration, Cmax and exposure increased lower than dose proportionally between 29 and 145 mg/kg. After a single s.c. dose of alofanib, animals showed moderate inter-individual variability, with mean CV of 47 (29 mg/kg) and 40% (145 mg/kg). Plasma levels were quantifiable up to 8 hours post 29 mg/kg dose in all animals. At a dose of 145 mg/kg, plasma levels were quantifiable up to 24 hours. Parenteral route (iv and s.c.) of alofanib administration is more preferable in clinical trials.

Citation Format: Ilya Tsimafeyeu, Mikhail Byakhov, Vlatka Bencetić Mihaljević, Jasna Padovan, Genoveva Murillo, Nadezhda Dragun, Evgenia Gavrilova, Sergei Tjulandin. Preclinical pharmacokinetic evaluation of alofanib for cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B084.