A Phase I Study Evaluating the Pharmacokinetic Profile of a Novel, Proprietary, Nano-formulated, Lower-Dose Oral Indomethacin

Abstract

Background: Safety and tolerability concerns associated with nonsteroidal anti–inflammatory drugs (NSAIDs) have prompted the development of lower–dose formulations. This phase 1 clinical study characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano–formulated, lower–dose oral indomethacin (nano–formulated indomethacin) compared with standard oral indomethacin in healthy subjects. Methods: Forty healthy subjects were enrolled in a single–dose, randomized, 5-period, 5-treatment crossover study. Subjects received nano–formulated indomethacin 20 mg (fasted), or nano–formulated indomethacin 40 mg or standard indomethacin 50 mg (fed and fasted). Pharmacokinetic parameters, including maximum measured plasma concentration (Cmax), time to maximum measured concentration (Tmax), elimination half–life (T1/2), and area under the concentration–time (AUC) curve, along with safety and tolerability, were assessed. Results: There was a more rapid mean (± standard deviation) Tmax for nano–formulated indomethacin 20 mg (1.11 ± 0.55 h) and 40 mg (1.25 ± 0.60 h) compared with indomethacin 50 mg (1.97 ± 0.81 h) under fasting conditions, demonstrating faster absorption for the nano–formulated indomethacin. The T1/2 was similar for nano–formulated indomethacin 40 mg and indomethacin 50 mg. The Cmax for nano–formulated indomethacin 40 mg was higher compared with indomethacin 50 mg in fasted subjects (3115 ± 900 ng/mL vs 2759 ± 936 ng/mL, respectively), and slightly lower in fed subjects (1360 ± 424 ng/mL vs 1408 ± 469 ng/mL, respectively). There was a 26% reduction in drug exposure (AUC0-∞) when subjects received nano–formulated indomethacin 40 mg compared with indomethacin 50 mg under fasting conditions (6861 ± 1585 h*ng/mL vs 9306 ± 2234 h*ng/mL, respectively). Safety and tolerability were comparable between formulations. Conclusion: The nano–formulated, lower–dose indomethacin had an improved PK profile compared with indomethacin. Under the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may support use of lower–dose NSAID formulations that improve safety/tolerability while maintaining pain relief similar to standard NSAID formulations.