Pharmacokinetic analysis of the FAK scaffold inhibitor C4 in dogs.
Inhibition of focal adhesion kinase-vascular endothelial growth factor receptor 3 complex by C4 was previously shown to reduce tumor growth alone and synergistically with other chemotherapeutic agents in animal tumor models. Single and multiple dose IV and oral dosing studies were performed in dogs to determine C4 pharmacokinetics. C4 was administered to 4 dogs at 1.25 or 2.50 mg/kg IV, or 7.50 mg/kg oral gavage. Single- (IV and oral) and multiple- (IV) dose pharmacokinetic samples were collected on days 1 and 3 at pre-dose and 0.5, 1, 2, 4, 8, 24, 120, 144, and 168 h post-dose. C4 concentrations were determined using liquid chromatography with tandem mass spectral detection with a limit of quantitation of 2.50 pg/mL. Pharmacokinetics of C4 was characterized by a 3-compartment model with linear distributional and elimination clearances using Phoenix 64 WinNonlin 6.3. Mean C4 plasma concentration-time profiles revealed a triexponential decline following either IV or oral administration, independent of dose with no accumulation. For the 2.5 mg/kg dose, the median half-life was ~21 h. Median C max and area under the curve (AUC0-24) were similar for days 1 and 3. Oral bioavailability for formulations of PBS, TPGS, Maalox(®), and Pepcid(®) was greatest with TPGS (45 %), followed by Maalox(®) (42 %), Pepcid(®) (37 %), and PBS (30 %). The pharmacokinetic study revealed that C4 has linear pharmacokinetics and does not accumulate following multiple-dose administration. Characterization of C4 pharmacokinetics provides a better understanding of the novel targeted agent, which will help facilitate further development of C4.
PK/PD Core Resource, CGP L1-140, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. john.wilton@roswellpark.org.
John
J
Wilton
Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.|CureFAKtor Pharmaceuticals, LLC, Buffalo, NY, 14263, USA.
Elena
E
Kurenova
PK/PD Core Resource, CGP L1-318, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
Laura
L
Pitzonka
PK/PD Core Resource, CGP L1-318, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.|Celgene Corporation, Summit, NJ, USA.
Allison
A
Gaudy
Laboratory Animal Resource, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
Leslie
L
Curtin
Laboratory Animal Resource, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
Sandra
S
Sexton
Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.|CureFAKtor Pharmaceuticals, LLC, Buffalo, NY, 14263, USA.
William
W
Cance
PK/PD Core Resource, CGP L1-317, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
Gerald
G
Fetterly
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D011738:Pyrilamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D006634:Histamine H1 Antagonists; D051416:Focal Adhesion Protein-Tyrosine Kinases; D011738:Pyrilamine
Anti-tumor; Chloropyramine; FAK–VEGFR-3; LC–MS/MS; Protein–protein interaction inhibitor; Repurposing