Levomilnacipran Hydrochloride
Levomilnacipran hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on July 25, 2013. It was developed and marketed as Fetzima® by Forest Corporation.
The exact mechanism of the antidepressant action of Levomilnacipran is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of reuptake at serotonin and norepinephrine transporters. Non-clinical studies have shown that Levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is indicated for the treatment of major depressive disorder (MDD).
Fetzima® is available as extended-release, capsule for oral use, containing 20, 40, 80 or 120 mg of free Levomilnacipran. The recommended dose is 40 mg to 120 mg Levomilnacipran once daily with or without food.
Update Date：2016-03-15
- Drug Name：
- Levomilnacipran Hydrochloride
- Research Code：
- F-2695; Dextromilnacipran
- Trade Name：
- Fetzima®
- MOA：
- Serotonin and norepinephrine reuptake inhibitor (SNRI)
- Indication：
- Major depressive disorder (MDD)
- Status：
- Approved
- Company：
- Forest (Originator) , Pierre Fabre
- Sales：
-
$8 Million (Y2013)
- ATC Code：
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-07-25 | Marketing approval | Fetzima | Major depressive disorder (MDD) | Capsule, Extended release | Eq. 20 mg/40 mg/80 mg/120 mg Levomilnacipran | Forest |
Update Date：2015-08-27
|
Molecular Weight | 282.8 | ||||||||||||
| Formula | C15H22N2O•HCl | |||||||||||||
| CAS No. |
96847-55-1 (Levomilnacipran ); 175131-60-9 (Levomilnacipran HCl); |
|||||||||||||
| Chemical Name | (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide | |||||||||||||
| Levomilnacipran （Free Acid/Base）Parameters： | ||||||||||||||
|
||||||||||||||
| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-12-22
1. US4478836A.
Update Date：2016-06-07
Mechanism of Action
Levomilnacipran, an active enantiomer of milnacipran, is a potent and selective SNRI with no appreciable binding
affinity or uptake inhibition potential at the dopamine transporter.
Levomilnacipran selectively bound to human norepinephrine transporters (hNET, Ki = 91 nM) and human serotonin transporters (hSERT, Ki = 11 nM, and inhibited reuptake of norepinephrine (IC50 = 11 nM) and serotonin (IC50 = 19 nM) in cell based in vitro assay.
Levomilnacipran had no apparent affinity (IC50>10 μM) for adrenergic, muscarinic, cholinergic, histaminergic receptors and ion channels including sodium, potassium, calcium and chloride channels.
In Vivo Efficacy
Levomilnacipran increased extracellular levels of NE and 5-HT in the prefrontal cortex of SD rats:
● Increased NE, 5-HT and DA level 2-3 fold at 20 mg/kg p.o..
● The minimal effective concentrations were 1 µM and 10 µM for NE and 5-HT.
Levomilnacipran showed antidepressant-like and anxiolytic-like efficacy in depression models:
● In NMRI mice: at 16 mg/kg p.o. in the forced swim test and at 2.5 mg/kg p.o. in the tail suspension test.
● In Swiss mice: at 3 mg/kg i.p. in the forced swim test.
● In conditioned USVs rats: The minimal effective dose was 5 mg/kg i.p. and the ED50 = 3.95-4.2 mg/kg.
Update Date：2016-06-07
Absorption of Levomilnacipran
Exhibited a linear pharmacokinetics in humans following oral dosing. The increases in Cmax and AUC appeared to be dose-proportional in the dose range of 40 to 120 mg levomilnacipran.
Had a high bioavailability in rats (71.4%-100%) and monkeys (100%).
Was absorbed rapidly (Tmax = 0.25-4 h) in mice, rats and monkeys, but slowly in humans (Tmax = 6-8 h).
Showed a half-life of 12.4-12.7 h in humans and 15-18 h in mice, longer than those in rats (0.9-3.4 h) and monkeys (5.9-6.2 h).
Had a high clearance in rats (4.6 L/h/kg) and mice (4.9 L/h/kg), but low in monkeys (0.2 L/h/kg), compared to liver blood flow after intravenous administration. The Cl/F in humans was 23.5-24.2 L/h after oral administration.
Exhibited an extensive distribution in mice, rats, but moderate in monkeys, with the apparent volume of distribution at 8.7, 5.5 L/kg and 0.9 L/kg, respectively, after intravenous administration. The apparent volume of distribution in humans was 405-444 L.
Distribution of Levomilnacipran
Exhibited low plasma protein binding (21.7%), human serum albumin (12.8%), γ-globulin (3.1%) and α1-acid glyco-protein (6.3%).
SD and Lister Hooded (pigmented) rats after oral administration: [10]
● The drug had a rapid and extensive distribution into most tissues, including central nervous system.
● Relatively higher concentration levels were observed in gastrointestinal tract, liver, kidneys, and the highest radioac-tivity in the brain was observed in the thalamus.
● Binding to the melanin of the pigmented tissues was evident with levels in the eye choroid layer and pigmented fur still presented at 168 h post-dose.
● Elimination of radioactivity from tissues was complete in the majority of tissues by 72 h post-dose.
Metabolism of Levomilnacipran
Metabolism of levomilnacipran by human liver microsomes, human hepatocytes, and recombinant human CYP enzymes was slow and limited.
CYP3A4 was the major metabolizing enzyme, with low contribution of other CYPs (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1). [12]
Overall, the parent drug represented the most abundant component, with N-desethyl levomilnacipran (F17400) as the major metabolite in human plasma.
All the identifiable metabolites found in humans were also found in non-clinical species.
The metabolites (e.g., N-desethyl levomilnacipran, F17400) were not pharmacologically active.
Excretion of Levomilnacipran
Was predominantly eliminated in urine, with the parent drug as the major component in urine in mouse, rat, monkey and human.
Levomilnacipran and its metabolites were eliminated primarily by renal excretion, with N-desethyl levomilnacipran (F17400) was the major metabolite excreted in the urine of humans, mice, rats and monkeys.
Drug-Drug interaction
Levomilnacipran had week inhibition for CYPs (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4/5), with IC50 >30 µM.
Levomilnacipran did not induce the enzyme activities of CYP1A2, 2C9, 2C19, 3A4/5 and UGT1A6.
Levomilnacipran was a substrate of P-gp and BCRP, but not an inhibitor.
Levomilnacipran was not a substrate and inhibitor of OAT, OATPB and OCT.
Major metabolite N-desethyl levomilnacipran was neither a substrate nor an inhibitor for P-gp, OAT1, OAT3 and OCT2.
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral administration of levomilnacipran in different species:
● Mouse lethal dose: 140 mg/kg
● Rat lethal dose: 215 mg/kg
Repeated-Dose Toxicity
Repeated-dose oral administration of levomilnacipran in different species from 1 to 52 weeks:
● For rats: The NOAEL was 30 (2 × MRHD) and 100 mg/kg/day (14 × MRHD) for males and females, respectively, determined by the 26-week study.
● For monkeys: The NOAEL was 30 mg/kg/day (8 × MRHD), determined by the 52-week study.
● Toxicity findings included several clinical signs, decreased body weight gains as well as liver lesions (minimal-to-mild centrilobular hypertrophy/vacuolation) in both rats and monkeys, but mainly seen at high doses.
Safety Pharmacology
Safety pharmacology assessments included in vitro and in vivo effects of levomilnacipran on central nervous system, cardiovascular system and respiratory system in multiple non-clinical species:
● The neurobehavioral effects were consistent with mechanism of action, and consisted of mydriasis, sedation, loss of traction, decreased muscle tone, decreased motor activity, decreased arousal and a dose-dependent decrease in body temperature at low to moderate doses and convulsions and death at higher doses (mice).
● Levomilnacipran significantly interfered in heart rate, blood pressure and ECG in freely moving dogs and conscious monkeys.
● With regard to respiratory safety, levomilnacipran had no significant effects on respiratory parameters, except at the high dose which associated exposure was ~25-fold higher than that at MRHD.
Genotoxicity
Levomilnacipran was not mutagenic in the Ames test or in mouse lymphoma assay. Likewise, it was not clastogenic in the in vivo micronucleus assay in rats up to 160 mg/kg/day.
Reproductive and Developmental Toxicity
Fertility and early embryo development: The NOAEL was 100 mg/kg/day for gonadal function, mating behavior, reproductive performance and early gestation in male and female rats, which was 8 × MRHD of 120 mg/day (on a mg/m2 basis).
Embryo-fetal development: There were maternal toxicities at high dose in rats and rabbits, based on reduced body weight gains and food consumption; The developmental NOAEL in rats and rabbits was the mid dose of 30 and 100 mg/kg/day, based on lower fetal weight and delayed ossification of sternebrae in rats, and delayed ossification of digit bones in rabbits at the high dose of 100 mg/kg/day, a dose 2.4 and 5 times the MRHD, respectively.
Pre- and Postnatal development in rats: The maternal toxicity was limited to decreased weight gains and food consumption at the mid and high doses; There was slight delay in physical development in the mid and high dose F1 pups, yet no effects on intellectual and sexual maturation; The NOAEL for maternal and offspring toxicity on F1 was 7 mg/kg/day (0.6 × MRHD).
The transfer of levomilnacipran and its metabolites to milk was evaluated after administering a single oral dose (5 mg/kg) of [14C]levomilnacipran to lactating female rats. A small portion was secreted into milk; the highest concentration of radioactivity was observed at 0.5 h post-dose (2674 ng eq/mL) and decreased rapidly to 44 ng eq/mL at 24 h post-dose. Small amount of N-desethyl levomilnacipran metabolite (F17400) was also observed in the milk (331 ng eq/mL) at 0.5 h post-dose.
Carcinogenicity
The carcinogenic potential of levomilnacipran was assessed in a standard 2-year study in SD rats and in a short-term (6-month) study in Tg.rasH2 mice.
● No significant carcinogenicity risk.
