Which bioequivalence study for a racemic drug? Application to milnacipran
- 99 Downloads
Milnacipran, a new non tricyclic antidepressant drug, is a racemic mixture (F2207) composed of two enantiomers: F2695 and F2696, both demonstrated to be active. A randomized open label, single-dose latin square study was undertaken in 24 healthy volunteers to compare, based on racemate data, the relative bioavailability of two new formulations to that of a reference formulation. Later on, as suggested by actual regulatory trend, analysis was carried out on enantiomer data, although in a supportive way. Bioequivalence was assessed on calculation of 90% confidence intervals for log-transformed Cmax and AUC(0−∞) and on Wilcoxon test for Tmax with a 5% level of significance. Based on racemate data, both test formulations were demonstrated to be equivalent to the reference capsule in terms of Cmax and AUC(0−∞). Differences in Tmax reached statistical significance, although their mean magnitude was small, and probably not relevant when related to antidepressant long-term therapy. When considering the test capsule — reference capsule comparison, the equivalence demonstrated for the racemate reflect that of each enantiomer. On the contrary, equivalence between the test tablet and the reference capsule demonstrated for the racemate, is not supported by both enantiomers as Cmax of F2696 fails to reach bioequivalence criteria, making more uncertain the conclusion of bioequivalence. From this experience, it seems than when equivalence is demonstrated close to the limits for the racemat e, it is difficult, especially for a low variability drug such as milnacipran, to comply with equivalence criteria for both enantiomers.
KeywordsBioequivalence racemic drug enantioselective analysis
Unable to display preview. Download preview PDF.
- 2.Puozzo C, Duchene P, Bromet M, Filaquier C, Zorza G. (1996): Determination of milnacipran (F2207) and its glucuroconjugate in plasma, blood and urine by high performance liquid chromatography with fluorescence detection.J Chromatogr. To be published.Google Scholar
- 3.Ung HL, Briem S, Puozzo C. (1996) Enantioselective determination of the two enantiomers of milnacipran (F2207) in plasma and urine by gas chromatography-mass spectrometry.J Chromatogr. To be published.Google Scholar
- 4.Rowland M. Tozer, T.N., (1980) Clinical pharmacokinetics: Concepts and applications ed. Lea & Febinger, Philadelphia.Google Scholar
- 7.Westlake W.J. (1988) Bioavailability and bioequivalence of pharmaceutical formulations. ed. Peace. Biopharmaceutical statistics for drug development. Marcel Dekker, New-york 329–352.Google Scholar
- 9.Benet L.Z. (1993) Bioavailability and bioequivalence: definitions and difficulties in acceptance criteria. In: Midha K.K., Blume H.H. (eds) Bio-international. Medpharm, Stuttgart.Google Scholar