| Autor: |
Midha, K. K., Rawson, M. J., McKay, G., Hubbard, J. W. |
| Předmět: |
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| Zdroj: |
International Journal of Clinical Pharmacology & Therapeutics; 2005, Vol. 43 Issue 5, p244-254, 11p |
| Abstrakt: |
Objective: To examine the effect of the exposure measures Cmax (peak exposure), AUCE (early exposure) and AUC (total exposure) on the bioequivalence of two sustained re lease formulations of bupropion (i) in the fasted state and (ii), after a high fat meal. The ratio Cmax/AUC (sensitive to rate of absorption) was also evaluated. Methods: A two-formulation, two-sequence, four-period replicate design study was per formed in 29 healthy men and women after an over night fast. Similarly, a two-period study was performed in 20 healthy men and women after ingestion of a high fat break fast. Plasma concentrations of bupropion were measured by HPLC/MS/MS and the data were analyzed (SAS PROC MIXED) by the Schuirmann-Sattersthwaite procedure (four-period study) and by the two one-sided test procedure (SAS PROC GLM) (two-period study). Standard bioequivalence limits of 80–125% were applied to all measures including AUCE and Cmax/AUC. Results: In the fasting study, the mean plasma concentration vs. time curves from (including over the first 24 hours) following the two administrations of each formulation were similar although there was a significant difference in median tmax between formulations. This may have contributed to a low estimate of geometric mean ratio (GMR) for AUCE (69%) which was judged to have failed bioequivalence. There was also rather low GMRs for Cmax (88%) and Cmax/AUC (89%) but these mea sure passed be cause the within-subject variabilities (WSV) were relatively low (19.6% and 11.2%, respectively). Total exposure (AUClast) met standard bio-equivalence limits of 80–125% easily. The raw data from the two-period fed also showed differences in the shapes of the plasma concentration vs. time curves around Cmax although there was no difference in median tmax. The WSV at median tmax was high (34%) as was the GMR (117%) for AUCE which failed, as did Cmax (GMR 112%). The WSV was very high at early time points be fore settling into a ‘plateau’ at about 11%. Discussion: There was no ‘spike’ in the plasma concentration vs. time pro files up to median tmax or be yond and there fore there was no evidence of dose dumping of the test formulation in either fasted or fed states. No bio equivalence limits have been set for AUCE but the application of standard BE limits of 80 to 125% meant that the fed study was clearly under powered given the high WSV at early time points. Conclusions: More re search is needed on the interesting concept of early exposure. The WSV is of ten high at median tmax which means that standard bioequivalence limits of 80–125% may be inappropriate. Despite the lack of dose dumping, application of AUCE to the fasting study, would have resulted in failure to declare bioequivalence since the GMR for this mea sure was only 69.5%. Application of a 90% confidence interval to AUCE to the fed study would have required powering to cope with the fact that this mea sure was highly variable. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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