Pharmacokinetic and bioequivalence comparison between orally disintegrating and conventional tablet formulations of flurbiprofen: a single-dose, randomized-sequence, open-label, two-period crossover study in healthy Chinese male volunteers.
BACKGROUND
Flurbiprofen, an NSAID, is used for the treatment of inflammation and pain caused by rheumatoid arthritis and osteoarthritis as well as soft-tissue injuries. A new orally disintegrating tablet (ODT) of flurbiprofen has recently been developed; this study was conducted to provide support for this drug to obtain marketing authorization in China.


OBJECTIVE
The aim of the study was to compare the pharmacokinetic properties and bioequivalence of flurbiprofen 50-mg ODT (test) with a conventional flurbiprofen 50-mg tablet (reference) under fasting conditions in healthy volunteers.


METHODS
This was a single-dose, randomized-sequence, open-label, 2-period crossover study. Healthy, nonsmoking Chinese male volunteers were randomly assigned to receive 150 mg (administered as three 50-mg tablets) of either the test or reference formulation of flurbiprofen, followed by a 7-day washout period and administration of the alternate formulation. Study drugs were administered after a 12-hour overnight fast. Blood samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. Serum flurbiprofen concentrations were analyzed using a validated nonstereospecific liquid chromatography/tandem mass spectrometry method. Pharmacokinetic parameters, including C(max), T(max), t(1/2), AUC(0-24), and AUC(0-infinity), were calculated and analyzed statistically. C(max), AUC(0-24), and AUC(0-infinity) were used to test for bioequivalence after natural logarithm (ln)-transformation. Tolerability was evaluated throughout the study by clinical assessments, vital sign monitoring, physical examinations, 12-lead ECG, clinical laboratory tests, and questioning subjects about adverse events (AEs).


RESULTS
A total of 20 Chinese males (mean [SD] age, 21.4 [2.5] years [range, 19-28 years]; height, 174.4 [4.2] cm [range, 169-183 cm]; weight, 63.2 [5.1] kg [range, 56-78 kg]; body mass index, 20.8 [1.4] kg/m(2) [range, 19-24 kg/m(2)]) completed the study. No period or sequence effect was observed. The 90% CIs for the ln-transformed ratios of Cmax, AUC(0-24), and AUC(0-infinity) were 99.9% to 115.9%, 97.8% to 107.9%, and 100.3% to 110.9%, respectively, meeting the predetermined criteria for bioequivalence. Two subjects (10.0%) experienced 1 of 2 mild AEs (increase in total bilirubin and dizziness), which were not considered to be associated with study drug administration.


CONCLUSIONS
This single-dose 150-mg (three 50-mg tablets) study of each formulation of flurbiprofen found that the test and reference products met the regulatory criteria for bioequivalence in these fasting healthy Chinese male volunteers. Both formulations were generally well tolerated. State Food and Drug Administration of China study registration number: 2005L04356.
Liu
Yan-Mei
YM
Shanghai Xuhui Central Hospital, Shanghai, China 200031.
Liu
Gang-Yi
GY
Liu
Yun
Y
Li
Shui-Jun
SJ
Jia
Jing-Ying
JY
Zhang
Meng-Qi
MQ
Lu
Chuan
C
Zhang
Yong-Mei
YM
Li
Xue-Ning
XN
Yu
Chen
C
D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D002681:China; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D005480:Flurbiprofen / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013607:Tablets; D005480:Flurbiprofen