P-043 - NTM-001 (Ketorolac Tromethamine 24 Hour Continuous Infusion): A 48-Hour Toxicity and Toxicokinetic Study in Minipigs, with a 14-Day Recovery Period

Abstract Title: NTM-001 (Ketorolac Tromethamine 24 Hour Continuous Infusion): A 48-Hour Toxicity and Toxicokinetic Study in Minipigs, with a 14-Day Recovery Period

Background: NTM-001 (Ketorolac Tromethamine 24 Hour Continuous Infusion) is a late-stage investigational novel intravenous (IV) formulation of the potent NSAID ketorolac being developed by Neumentum, Inc. as a convenient-to-use pre-mixed bag designed to deliver 24 hours of opioid-level analgesia, reduce the potential analgesic gap associated with bolus ketorolac, reduce or eliminate the need for postoperative opioids, and shorten the length of hospital stay. It’s novel alcohol-free formulation is also expected to eliminate the pain associated with traditional alcohol-containing bolus ketorolac.

Purpose/Objectives: To evaluate the toxicity and toxicokinetic profile of a 48-hour continuous IV infusion of NTM-001 to male and female Göttingen minipigs, and to assess reversibility of any effects over a 14-day dose-free period. The study included a 0.9% sodium chloride control group.

Methods: The work was performed at Frontage Laboratories, Inc. (Exton, PA). Minipigs received NTM-001 or vehicle (0.9% saline) by infusion for a target of 48 consecutive hours or ketorolac tromethamine USP by repeat bolus administrations (~6 hours for a total of eight doses). Prior to infusion, the NTM-001-dosed animals were administered a loading dose at a target of 13.75 mg (of the designated formulation) over 30 to 60 seconds. The vehicle control animals received a volume of 0.9% saline equivalent to that administered to the Group 2 (NTM-001 low-dose) animals. There were six minipigs/sex in each group, with four minipigs/sex/group terminated the day after completion of dosing (Day 4) and 2 minipigs/sex/group terminated 14 days after completion of dosing (Day 17). Parameters evaluated included: clinical observations, body weights, food consumption, clinical pathology (hematology, coagulation, serum chemistry, urine chemistry and urinalysis), organ weights, macroscopic pathology, and selected tissues for microscopic pathology. Plasma samples for toxicokinetic assessment were analyzed for ketorolac concentration according to validated LC-MS/MS method BA-TM-0136.

Results: Due to technical issues, dosing was not continuous for nine minipigs, seven more received less than the intended dose, and two animals required extended infusion to achieve full dosing. All other animals received the full dosage with no interruptions. The mean administered NTM-001 doses were 0, 29.6, 140.9, and 279.1 mg/kg for Groups 1-4, respectively. The mean administered ketorolac tromethamine, USP dose was 30.1 mg/kg. For Groups 2, 3, and 4, T_max and elimination half-life values were similar between males and females among groups. Exposure (C_max and AUC) increased dose proportionally with increasing dose. Dose-normalized exposure (dose-normalized C_max and AUC) was similar among Groups 2, 3, and 4 (males and females). For Group 5, T_max and elimination half-life values were similar between males and females. For Group 5, dose-normalized exposure (dose-normalized C_max and AUC) was similar between males and females and was higher than dose-normalized exposure for Groups 2, 3, and 4. All animals survived to the scheduled necropsies. There were no NTM-001-related effects on body weight, hematology, coagulation, urinalysis, or macroscopic findings. Adverse effects were limited to clinical observations of lethargy and reduced activity for a single high-dose male.

Conclusions/Implications for future research and/or clinical care: Minipigs were administered a 48-hour continuous IV infusion of NTM-001 for total mean doses of 0, 29.6, 140.9, and 279.1 mg/kg. The no-observed adverse-effect level (NOAEL) was considered to be 140.9 mg/kg (combined sexes). Dose-normalized exposure (AUC_last/dose) at the NOAEL in males and females, was 917 ± 280 and 1650 ± 871 hr*kg*ng/mL/mg, respectively.

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