Abstract 4513: Pharmacokinetics and pharmacodynamics of indenoisoquinoline LMP400 (Indotecan) in BALB/c female mice bearing CT-26 colon tumors
Authors: Guo Jianxia , Holleran Julianne , Schmitz John C. , Czambel Kenneth , Beumer Jan H. , Eiseman Julie L. 
Published: August 2015

Abstract
Introduction: The indenoisoquinoline, LMP400 (NSC743400, indotecan), is currently in Phase I clinical trials for the treatment of solid tumors and is administered as an IV infusion. The compound is an inhibitor of topoisomerase I (TOP1) and does not appear to be a substrate for BCRP (ABCG2) or P-gp (ABCB1). In this study, we evaluated the plasma pharmacokinetics and tissue distribution of LMP400 and the tumor expression of TOP1 and γH2AX in mice bearing CT26 murine colon tumors after either IV or PO administration of LMP400.
Methods: CT26 murine colon tumors were implanted in female BALB/c mice and 3 weeks after tumor implantation, the mice were administered 18 mg/kg LMP400 IV or PO. Blood and tissues were collected between 5 and 2880 min after IV dosing or 5 and 1440 min after PO dosing. Blood was centrifuged to obtain plasma. Tumor samples for TOP1 ELISA were snap-frozen within 2 min after euthanasia of the mice while other tissues were weighed prior to being frozen in liquid N2. Concentrations of LMP400 were determined by LC-MS/MS and non-compartmental analysis was performed using PK solutions. Bioavailability was calculated from plasma AUC (0-∞). Tumor samples were analyzed by western blot for TOP1 and γH2AX concentrations and by ELISA for TOP1.
Results: Plasma Cmax occurred at 5 min (4633 ± 505 ng/mL) after IV and 15 min (890 ± 279 ng/mL) after PO administration. Plasma AUC0-∞ for IV and PO were 1639 or 628 μg•min/mL, respectively. Plasma t1/2 for IV and PO were 1515 min and 312 min, respectively. Clearances for LMP400 IV and PO in plasma were 16 and 29 mL/min/kg, respectively. Oral bioavailability was 58%. After administration of LMP400 IV, AUC0-∞ in tumor, liver, kidney, lung, brain, skeletal muscle and fat were 11324, 48670, 54789, 65242, 3009, 5710 and 10849 μg•min/mL, respectively. After administration of LMP400 PO, AUC0-∞ in tumor, liver, kidney, lung, brain, skeletal muscle and fat were 2711, 6802, 4037, 3715,1066, 804, and 5882 μg•min/mL, respectively. TOP1 in tumor was inhibited while γH2AX/H2AX was increased between 2h and 24h after either IV or PO dosing.
Conclusion: LMP400 is bioavailable after PO administration to mice and results in tumor inhibition of TOP1 and increases in γH2AX/H2AX ratios, suggesting that LMP400 could be effective if administered as an oral formulation.
Support: UM1CA186690 and P30-CA-47904
Note: This abstract was not presented at the meeting.
Citation Format: Jianxia Guo, Julianne Holleran, John C. Schmitz, Kenneth Czambel, Jan H. Beumer, Julie L. Eiseman. Pharmacokinetics and pharmacodynamics of indenoisoquinoline LMP400 (Indotecan) in BALB/c female mice bearing CT-26 colon tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4513. doi:10.1158/1538-7445.AM2015-4513