PIM2 is a serine/threonine protein kinase that has roles in cell growth, proliferation, and apoptosis via the regulation of multiple signal transduction cascades. JP_11646 is a novel PIM2 inhibitor that has shown antitumor activity against breast, colon, liver, lung, and pancreatic solid tumors, as well as multiple myeloma and leukemia. The pharmacokinetics (PK) of JP_11646 has not been described. Therefore, a PK study was conducted to characterize JP_11646 disposition in plasma and various tissues. Normal ICR (CD-1) mice received either single day or five consecutive days of 15 - 25 mg/kg JP_11646 via intraperitoneal (IP) or intravenous (IV) administration. Plasma samples were collected at serial time points (0.5, 1, 2, 4, 6, and 8 hrs) following a single dose of 20 mg/kg IV or 25 mg/kg IP JP_11646 administration. Plasma and various tissues (brain, heart, kidney, lung, liver, muscle, colon, pancreas, and spleen) were collected at serial time points following multiple daily doses of 15 mg/kg IP JP_11646 on day five. Three mice were euthanized per time point on each collection day. JP_11646 concentrations were determined by a validated LC-MS/MS method, with a LLOQ of 1 ng/ml. Noncompartmental PK analysis was performed using Phoenix 64 (Pharsight, WinNonlin 6.3). Following single dose administration of JP_11646 of 20 (IV) and 25 mg/kg (IP), mean plasma Cmax was 6,951 and 6,630 ng/ml, respectively. Mean plasma drug exposures (AUCinf) were 11,065 and 11,024 ng-hr/ml, respectively, resulting in similar drug exposure between the IV and IP route. To compare plasma and tissue exposure following multiple dose administration, JP_11646 was given at 15 mg/kg IP. The mean plasma Cmax was 4,601 ng/ml., while the mean Cmax in colon, pancreas, and spleen were 24,523, 77,811, and 18,835 ng/ml, respectively. The half-life of JP_11646 in plasma and tissues ranged from 0.8 - 3 hrs. Tissue exposure in colon, pancreas, and spleen was 48,792, 157,273, and 40,511 ng-hr/ml, respectively. The pancreas to plasma partition coefficient (Kp) of 20.6 demonstrates that the pancreas receives the highest exposure to JP_11646. The drug also distributes to the colon and spleen, with Kp values of 6.4 and 5.3, respectively. JP_11646 PK appears linear and the half-life ranges from 0.8 - 3.0 hrs. JP_11646 distributes widely to tissues, with the highest drug exposure in the pancreas, spleen, and colon. These results give insight into tumor types with potential for optimal antitumor therapy with JP_11646.
Citation Format: Laura B. Pitzonka, Allison Gaudy, Sarah Schihl, Leslie Curtin, Sandra Sexton, Carmen M. Baldino, Justin Caserta, Yvonne Flanders, Stephane Dumas, Gerald Fetterly. Investigation of the pharmacokinetic profile of the novel PIM2 inhibitor, JP_11646. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4647. doi:10.1158/1538-7445.AM2014-4647