PHARMACOKINETICS OF MILNACIPRAN IN LIVER IMPAIRMENT

The pharmacokinetics of single 50 mg oral and intravenous doses of mil nacipran, a new non tricyclic antidepressant drug, were compared in 11 chronic liver impaired (LI) subjects and in 6 control subjects. Hepat ic impairments, classified according to the PUGH scale were moderate ( 1 grade A), intermediate (6 grade B) and severe (4 grade C). Concentra tions of unchanged drug and its conjugated form (its main metabolite) were measured in plasma and urines. In control subjects, milnacipran p resent high absolute bioavailability (mean value of 90%). Around 50% o f the dose are excreted in urines as unchanged, while around 14% are e xcreted as glucuroconjugate. The remaining is composed of free and con jugated phase I inactive metabolites. Administration of milnacipran in LI subjects results in non significant changes in its pharmacokinetic s, although its variability is increased. Unchanged drug exposure is n ot modified in LI subjects, while plasma levels of the conjugate are s lightly decreased compared to the control group. This could either be due to a slight reduction in the conjugation process, or to a change i n the distribution of the drug as urine excretion of both unchanged an d conjugated forms are not modified compared to the control group. A f ew LI subjects present supra-bioavailability resulting in higher drug exposure after oral administration than after intravenous infusion. Th ese modifications are not clinically relevant as drug exposure of the parent drug is not modified. As the unchanged drug is the only compoun d responsible for the activity of milnacipran, no dosage adjustment is needed in patients presenting liver impairment.