A Novel Formulation of Ketorolac Tromethamine (NTM-001) in Continuous Infusion in Adults with and without Renal Impairment: A Randomized Controlled Pharmacologic Study

• Published in: Advances in therapy 2024-09, Vol.41 (9), p.3633-3644
• Main Authors: Pergolizzi, Joseph V., Batra, Amanjot, Schmidt, William K.
• Format: Article
• Language: English
• Subjects: Cardiology; Endocrinology; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original Research; Pharmacology/Toxicology; Rheumatology
• ISSN: 0741-238X; 1865-8652; 1865-8652
• DOI: 10.1007/s12325-024-02933-7

Introduction There is a medical need for a safe, effective nonopioid postoperative analgesic for older subjects, including those with mild to moderate renal impairment. Methods Participants (≥ 65 years) were stratified by no, mild, or moderate renal impairment defined as creatinine clearance 60–89 mL/min for mild and 30–59 mL/min for moderate. Subjects were randomized to receive a loading dose of 6.25 mg of ketorolac tromethamine drug candidate NTM-001 followed by a 1.75 mg/h continuous intravenous (IV) infusion over 24 h or an IV bolus injection of ketorolac tromethamine (KETO-BOLUS) of 15 mg every 6 h. There were four treatment periods of 24 h for each subject with a minimum 7-day washout between them. This was a crossover study so subjects served as their own controls. Blood drawn from the subjects was used to plot concentration–time profiles against target profiles. Adverse events were monitored. Results Thirty-nine subjects enrolled. Concentration–time profiles showed low intersubject variability. Model-predicted curves for those with renal impairment closely matched observed plasma concentrations. Continuous infusion maintained higher mean plasma concentrations than the bolus regimen. No serious or unexpected adverse events were observed. No deaths occurred. Conclusions NTM-001 was considered safe and well tolerated in this population of participants ≥ 65 years, including in those with mild or moderate renal impairment. There were fewer adverse events in the continuous infusion group. The predictable pharmacologic properties and blood concentration levels suggest that continuous IV infusion of ketorolac can be used as an effective postoperative pain reliever in older subjects. Plain Language Summary Controlling postoperative pain can lead to faster recovery. Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID), like ibuprofen and naproxen, that can be as effective as morphine without the same risks. In hospitals, ketorolac is usually administered intravenously (IV) either continuously or as a bolus injection. A bolus of ketorolac may result in adverse gastrointestinal side effects. In this study, a new formulation of ketorolac tromethamine, NTM-001, was administered IV as a continuous 24 h infusion compared to IV boluses of ketorolac tromethamine every 6 h in volunteers. Volunteers were older (≥ 65 years) and had no, mild, or moderate kidney dysfunction. One randomized group received a starting IV dose of 6.26 mg followed by a cont