Pharmacokinetics of milnacipran in liver impairment

Abstract

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

Excretion and Metabolism of Milnacipran in Humans after Oral Administration of Milnacipran Hydrochloride

“…A major milnacipran metabolite, previously reported as milnacipran N-glucuronide (Puozzo et al, 1998), was ultimately identified in this study as l-milnacipran carbamoyl O-glucuronide. This major metabolite was excreted primarily in urine and accounted for approximately 17% of the dose.…”

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

“…Sensitivity is sufficient to quantify milnacipran in patients (50 mg b.i.d.) over at least four to five half-lives [8][9][10]. A typical pharmacokinetic profile of a subject administered 50 mg oral single dose is shown in Fig.…”

“…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].…”

Role and rationale for the use of milnacipran in the management of fibromyalgia

“…28 Pharmacokinetic studies indicate that dose adjustment is not necessary based on age, gender, mild-to-moderate renal impairment, 29 or mild-to-moderate hepatic impairment. 30 However, caution should be exercised in patients with moderate renal impairment or severe hepatic impairment. In patients with severe renal impairment, the maintenance dose of milnacipran should be reduced by approximately 50% to 50 mg/day (25 mg twice daily).…”