Abstract B146: Preclinical pharmacokinetic studies of RPT835, an allosteric FGFR2 inhibitor
| Autor: | Jasna Padovan, Mikhail Byakhov, Ilya Tsimafeyeu, Sergei Tjulandin, Vlatka Bencetić Mihaljević, Genoveva Murillo |
|---|---|
| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 14:B146-B146 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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 ( PK resultsStudyGroup (dose, mg/kg)C0/Cmax, ng/mlTmax, ht1/2AUC, h*ng/mLCL, mL/min/kgVss, L/kgF, %1iv, 3057739-0.93580386.76.9NC - Parameter cannot be calculatedoral/gavage, 3043.61-2NCNCNCNCNC2iv, 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- 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|