title: Pharmacokinetics and safety of low-dose submicron indomethacin 20 and 40 mg compared with indomethacin 50 mg.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors: PAREXEL International Corporation , Baltimore MD , USA.
authors: Kemi
authors: K
authors: Olugemo
authors: Daniel
authors: D
authors: Solorio
authors: Claire
authors: C
authors: Sheridan
authors: Clarence L
authors: CL
authors: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D002214:Capsules; D018592:Cross-Over Studies; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D055815:Young Adult
chemical_list: D002214:Capsules; D007213:Indomethacin
keywords: Acute pain; SoluMatrix; Tivorbex; indomethacin; pharmacokinetics; submicron