Which bioequivalence study for a racemic drug? Application to milnacipran

Abstract

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-infinity) 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-infinity). 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 racemate, it is difficult, especially for a low variability drug such as milnacipran, to comply with equivalence criteria for both enantiomers.

Pharmacokinetics of milnacipran in renal impairment

“…Parameters describing the pharmacokinetics of milnacipran in control subjects are in good agreement with previous observations made under similar conditions (3,8). As milnacipran is primarily eliminated via the renal route (Cl, / (CltoJF) = 0.5) with a strong active secretion process (CIR is 19.6 ± I.h-1 ) , it is not surprising that impaired renal function affects its pharmacokinetics.…”

Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

“…Examining the effects on functional outcomes in the fixed-dose study testing levomilnacipran 40, 80 and 120 mg/day (23), levomilnacipran 80 and 120 mg significantly improved SDS scores and the largest and most robust treatment effects were in the levomilnacipran 120 mg group. For functional remission, significant treatment advantage was found in patients with severe MDD (baseline MAD-RS score at least 35) who received the highest dosage of levomilnacipran (120 mg/day), with remission rates of 28% vs. 12%, resulting in a NNT of 7 (95% CI [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…Levomilnacipran is an active enantiomer of the racemic drug milnacipran (4,5); milnacipran itself is approved by the US FDA for the management of fibromyalgia (6) and in other countries for the treatment of MDD (7). MDD is a common disorder.…”

Determination of milnacipran, a serotonin and noradrenaline reuptake inhibitor, in human plasma using liquid chromatography with spectrofluorimetric detection

“…6), proving the specificity of the LC technique. It was further demonstrated that the major metabolic pathway of milnacipran in human went through glucuroconjugation [8,9]. Therefore, metabolites could not interfere with milnacipran because they were more polar and were early eluted.…”

“…The availability of a low cost bioanalytical method, easy to transfer and to set up, represents an advantage in therapeutic drug monitoring when required (control of compliance, overdose). The current method was used throughout the development of milnacipran and is, therefore, a pivotal reference when using pharmacokinetic data from major published trials [6][7][8][9][10][11].…”