Pharmacokinetics and safety of low-dose submicron indomethacin 20 and 40 mg compared with indomethacin 50 mg

Abstract

Introduction. Indomethacin is a potent analgesic that, similar to other nonsteroidal anti-inflammatory drugs, is associated with serious dose-related adverse events. There is a need for newer nonsteroidal anti-inflammatory drug products with improved tolerability. Low-dose submicron indomethacin was developed using SoluMatrix Fine Particle Technology™ to enable treatment at lower doses than commercially available indomethacin drug products. This study evaluated the pharmacokinetics and safety of submicron indomethacin 20 and 40 mg compared with indomethacin 50-mg capsules. Methods. This was a phase 1, randomized, open-label, 4-period, 4-sequence, single-dose crossover study. Forty healthy volunteers received low-dose submicron indomethacin 20- or 40-mg capsules, or indomethacin 50-mg capsules under fasting or fed conditions. Pharmacokinetic parameters and safety were assessed. Results. Comparable fasting peak plasma levels (mean ± standard deviation) were demonstrated for submicron indomethacin 40 mg (2368.79 ± 631.38 ng/ml) and indomethacin 50 mg (2369.40 ± 969.06 ng/ml). The overall systemic exposure (geometric least squares mean; 95% CI) was > 21% lower for submicron indomethacin 40 mg (6007.71 ng·h/mL; 5585.73–6461.58) compared with indomethacin 50 mg (7646.23 ng·h/ml; 7110.44–8222.40) under fasting conditions. Food delayed the rate but did not affect the extent of indomethacin absorption from submicron indomethacin 40 mg. Submicron indomethacin 40 mg administration resulted in earlier time to peak plasma levels (median 1.67; min–max 0.5–3.5 hours) under fasting conditions compared with indomethacin 50 mg (2.02; 0.5–5.0 hours). Submicron indomethacin 20 and 40 mg were dose proportional and generally well tolerated. Conclusion. Compared with indomethacin 50 mg, submicron indomethacin 40 mg achieved similar peak plasma concentrations, lower systemic exposure, and a faster time to peak plasma concentration, indicating rapid absorption. The current formulation of low-dose submicron indomethacin has recently demonstrated efficacy in 2 phase 3 studies in patients with acute pain following bunionectomy and represents a new, low-dose treatment option for patients with acute pain.

Keywords :

• Acute pain
• indomethacin
• pharmacokinetics
• SoluMatrix
• submicron
• Tivorbex

Acknowledgements

This study was funded by Iroko Pharmaceuticals, LLC (Philadelphia, PA). The authors thank Dave Dickason, Iroko Pharmaceuticals, and the patients and investigators who participated in this study. Medical writing support was provided by Ewa Wandzioch, PhD, and Colville Brown, MD (AlphaBioCom, LLC, King of Prussia, PA), and funded by Iroko Pharmaceuticals.

Declaration of interest

K. Olugemo was an employee of PAREXEL International Corp., which was contracted to perform this study. The study was sponsored by Iroko Pharmaceuticals, LLC. C. Sheridan, D. Solorio, and C. Young are employees of Iroko Pharmaceuticals.