Abstract 3372: Pharmacokinetic analysis of CFAK-C4 in dogs and estimation of first dose in man.
Authors: Gaudy Allison , Wilton John , Curtin Leslie , Kurenova Elena , Buitrago Sandra , Cance William , Fetterly Gerald 
Published: August 2014

Purpose: Inhibition of the FAK-VEGFR-3 interaction by the small molecule inhibitor chloropyramine hydrochloride (CFAK-C4) has been shown to reduce tumor growth both alone and synergistically with doxorubicin and gemcitabine in an animal tumor model. A multiple dose study of CFAK-C4 in dogs was investigated to gain knowledge in estimating a first in man dose. Methods: CFAK-C4 was given to two female and two male dogs as an IV infusion at 1.25 or 2.5 mg/kg for five minutes, on three consecutive days, days 1, 2 and 3. Single- and multiple-dose PK samples were collected on days 1 and 3 of dosing. Plasma samples were collected at 0.5, 1, 2, 4, 8, and 24 hours post-dose. CFAK-C4 concentrations were determined using LC-MS/MS, with a LLOQ of 2.5 pg/ml. Noncompartmental PK analysis was performed using WinNonlin (Pharsight, version 5.3).

Results: The mean CFAK-C4 plasma concentration-time profiles revealed a biexponential decline of drug following IV infusion, independent of day of dosing. The median (range) half-life was 3.42 hours (2.75-4.06 hours) and 3.79 (3.5-5.0) on days 1 and 3 following administration of 1.25 mg/kg CFAK-C4. At the 2.5 mg/kg dose level, the median half-life was similar. The median (range) Cmax of 1.25 mg/kg CFAK-C4 was determined to be 75 ng/ml (41-87 ng/ml) on day 1 and 99 ng/ml (84-102 ng/ml) on day 3. After the 2.5 mg/kg dose the Cmax was 185 ng/ml (165-244 ng/ml) and 171 ng/ml (153-181 ng/ml) on days 1 and 3 respectively. The AUC0-24 at the 1.25 mg/kg dose level was similar on both days 1 and 3 with a median (range) of 167 ng*hr/ml (117-231 ng*hr/ml) and 178 ng*hr/ml (170-194 ng*hr/ml), respectively. The AUC0-24 was also similar after the 2.5 mg/kg dose on days 1 and 3 with a median (range) of 447 ng*hr/ml (434-495 ng*hr/ml) and 406 ng*hr/ml (400-460 ng*hr/ml), respectively. The median (range) clearance for dose 1.25 mg/kg was 7.46 L/hr/kg (5.36-10.59 L/hr/kg) on day 1 and 6.47 L/hr/kg (6.07-6.91L/hr/kg) on day 3. For the 2.5 mg/kg dose level, the median (range) clearance was slightly lower compared with the 1.25 mg/kg dose, with values of 5.48 L/hr/kg (5.02-5.66 L/hr/kg) and 5.85 L/hr/kg (5.04-5.93 L/hr/kg) on days 1 and 3, respectively. Utilizing allometric scaling techniques of PK parameters from mice and dogs for CFAK-C4, the estimated human PK parameters for volume of distribution, clearance and half-life were 1695 L, 126 L/hr, and 9.34 hours, respectively. Subsequently, using a no observable adverse event level (NOAEL) of 44.5 mg/kg IP for mice and a NOAEL of 2.5 mg/kg IV for dog, the human starting dose (assuming a 70 kg human) would be a daily dose of 25 mg and 10 mg based on mouse or dog, respectively. Given that dogs are the most sensitive species, 10 mg daily is the suggested first dose in man for CFAK-C4. Conclusions: These results demonstrate that CFAK-C4 has linear kinetics and that no accumulation of drug occurs after multiple dosing. Allometric scaling of mouse and dog data allowed for the estimation of the first in man dose of CFAK-C4.

Citation Format: Allison Gaudy, John Wilton, Leslie Curtin, Elena Kurenova, Sandra Buitrago, William Cance, Gerald Fetterly. Pharmacokinetic analysis of CFAK-C4 in dogs and estimation of first dose in man. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3372. doi:10.1158/1538-7445.AM2013-3372