Comparative bioavailability and pharmacokinetics of investigational enteric- and film-coated formulations of flurbiprofen 100-mg tablets: a single-dose, randomized, open-label, two-period, two-way crossover study in healthy Pakistani male volunteers

Abstract

Background: Flurbiprofen, a chiral, 2-arylpropionic acid NSAID with analgesic and antipyretic properties, has been associated with important gastrointestinal adverse events, including peptic ulcer and gastrointestinal perforation. An investigational enteric-coated tablet formulation of flurbiprofen was produced to evaluate whether it would improve the gastric tolerability of flurbiprofen.

Objective: This study compared the pharmacokinetic parameters and bioavailability of flurbiprofen from the investigational enteric-coated tablet (test) and from a film-coated immediate-release tablet compounded for the purposes of this study (reference).

Methods: This was a randomized, open-label, 2-period, 2-way crossover study conducted in healthy male volunteers at a single center in Pakistan. Small batches of the test and reference tablets were manufactured and evaluated according to US Pharmacopoeia criteria. Each volunteer received a single 100-mg tablet of the test and reference formulations, separated by a 14-day washout period. Tablets were administered after an overnight fast. Blood samples were obtained before dosing (0) and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 12, and 24 hours after drug administration. Safety monitoring was performed by an unblinded physician and included adverse events, biochemistry and hematology tests, urinalysis, and ECGs. Plasma concentrations of the 2 formulations were determined, and pharmacokinetic parameters were compared using noncompartmental analysis. The 2 formulations were considered bioequivalent if the 90% CI for the ratios (test:reference) of log-transformed C(max), AUC(0-t), and AUC(0-infinity) were between 0.80 and 1.25.

Results: Of the 23 healthy male subjects originally recruited, 2 withdrew before commencement of the study. Twenty-one subjects (mean [SD] age, 25.4 [2.7] years [range, 20-30 years]; weight, 63.4 [7.2] kg [range, 56-78 kg]) were enrolled in and completed the study. There were significant differences in C(max), AUC(0-t), and AUC(0-infinity) between the test and reference formulations (all, P < 0.001). The 90% CIs for the geometric mean ratios of log-transformed C(max), AUC(0-t), and AUC(0-infinity) (49.78-55.22, 57.51-64.42, and 58.48-65.30, respectively) were not within the predetermined bioequivalence range. There were no clinically meaningful changes in hematology, biochemistry, urinalysis, or physical variables with either formulation over the course of the study. Mild headache was reported in 2 volunteers who received the reference formulation during the first study period; this was not considered related to study drug.

Conclusions: In this small study in healthy Pakistani male subjects, there were significant differences in the bioavailability and pharmacokinetic parameters of the enteric- and film-coated tablet formulations of flurbiprofen. Thus, the 2 formulations could not be considered bioequivalent. Both formulations were well tolerated.