WHICH BIOEQUIVALENCE STUDY FOR A RACEMIC DRUG - APPLICATION TO MILNACIPRAN

Milnacipran, a new non tricyclic antidepressant drug, is a racemic mix ture (F2207) composed of two enantiomers : F2695 and F2696, both demon strated to be active. A randomized open label, single-dose latin squar e study was undertaken in 24 healthy volunteers to compare, based on r acemate data, the relative bioavailability of two new formulations to that of a reference formulation. Later on, as suggested by actual regu latory 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 C-max and AUC(0-infinity) and on Wilcoxon test for T-max with a 5% level of significance. Based on racemate data, both test formulations were demonstrated to be equivale nt to the reference capsule in terms of C-max and AUC(0-infinity). Dif ferences in Tm, reached statistical significance, although their mean magnitude was small, and probably not relevant when related to antidep ressant long-term therapy. When considering the test capsule - referen ce capsule comparison, the equivalence demonstrated for the racemate r eflect that of each enantiomer. On the contrary, equivalence between t he test tablet and the reference capsule demonstrated for the racemate , is not supported by both enantiomers as C-max of F2696 fails to reac h bioequivalence criteria, making more uncertain the conclusion of bio equivalence. From this experience, it seems than when equivalence is d emonstrated close to the limits for the racemat e, it is difficult, es pecially for a low variability drug such as milnacipran, to comply wit h equivalence criteria for both enantiomers.