Pharmacokinetics of milnacipran in renal impairment

The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.