Tasimelteon
Tasimelteon was approved by the U.S. Food and Drug Administration (FDA) on Jan 31, 2014. Then it was approved by European Medicine Agency (EMA) on July 03,2015. It was first found by Bristol-Myers Squibb, then developed and marketed as Hetlioz® by Vanda Pharmaceuticals.
Tasimelteon is an agonist at melatonin MT1 and MT2 receptors involved in the control of circadian rhythms. It is the first FDA approved medication for the treatment of non-24-hour sleep-wake disorder (Non-24).
Hetlioz® is available as capsulefor oral use, containing 20 mg of free Tasimelteon, and recommended dose is 20 mg prior to bed time without food.
Update Date：2016-03-14
- Drug Name：
- Tasimelteon
- Research Code：
- VEC-162
- Trade Name：
- Hetlioz®
- MOA：
- Melatonin receptor agonist
- Indication：
- Non-24-hour sleep-wake disorder (N24HSWD)
- Status：
- Approved
- Company：
- Vanda (Originator)
- Sales：
-
$44.3 Million (Y2015);
$12.8 Million (Y2014); - ATC Code：
Update Date：2016-01-25
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-01-31 | Marketing approval | Hetlioz | Non-24-hour sleep-wake disorder (N24HSWD) | Capsule | 20 mg | Vanda | Priority |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2015-07-03 | First approval | Hetlioz | Non-24-hour sleep-wake disorder (N24HSWD) | Capsule | 20 mg | Vanda | Orphan |
Update Date：2015-08-27
|
Molecular Weight | 245.32 | ||||||||||||
| Formula | C15H19NO2 | |||||||||||||
| CAS No. | 609799-22-6 (Tasimelteon); | |||||||||||||
| Chemical Name | (1R, 2R)-N-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide | |||||||||||||
| Tasimelteon （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-12-03
Update Date：2016-02-04
Update Date：2016-06-15
Mechanism of Action
Tasimelteon is a full agonist at melatonin receptors MT1 (Ki = 0.304 nM, IC50 = 0.586 nM) and MT2 (Ki = 0.0692 nM, IC50 = 0.133 nM).
Tasimelteon demonstrated potent, concentration-dependent inhibition of forskolin-stimulated cAMP accumulation (MT1, EC50 = 0.74 nM; MT2, EC50 = 0.1 nM).
The metabolite of tasimelteon showed nanomolar affinity at human melatonin receptor MT1 (M13, IC50 = 7.69 nM), and melatonin receptor MT2 (M11, IC50 = 6.63 nM; M12, IC50 = 20.8 nM; M13, IC50 = 1.78 nM; M14, IC50 = 8.42 nM).
Tasimelteon showed no significant blatonininding affinity for 63 and 170 different targets in two separate screens at 10 and 100 µM.[15,16]
Binding affinity of tasimelteon at the human melatonin receptors:
● In NIH-3T3 cell lines containing melatonin receptors:
v Human MT1 receptor: Ki = 0.35 nM.
v Human MT2 receptor: Ki = 0.17 nM.
● In CHO-K1 cell lines containing melatonin receptors:
v MT1 receptor: Ki = 0.304 nM.
v MT2 receptor: Ki = 0.0692 nM.
In Vivo Efficacy
The ex vivo study of brain slices taken from rats: Suprachiasmatic nucleus (SCN) electrical activity rhythms shifted significantly faster than those in slices from the vehicle-treated animals.
The model of acute phase shifting of locomotor activity in rats: Advanced the onset of running-wheel activity in rats.
The model of entrainment of “free-running” activity rhythms in rats: The onset of activity coincided with the injection time, ED50 = 0.21 mg/kg.
Update Date：2016-06-15
Absorption of Tasimelteon
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 1-300 mg tasimelteon.
Had good bioavailability in rats (58.5%) and humans (50%), but poor in monkeys (11.7%), after oral administrations.
Was absorbed quickly (Tmax = 0.25-1.25 h) in humans, female rats and monkeys.
Showed a half-life of 1.02 h in humans, shorter than those in rats and monkeys (2.1 h), after intravenous administrations.
Had high clearance in rats (5.3 L/h/kg), but moderate in monkeys (1.6 L/h/kg) and humans (505 mL/min), in contrast to liver blood flow, after intravenous administrations.
Exhibited an extensive tissue distribution in rats, monkeys and humans, with apparent volumes of distribution at 3.8, 1.4 L/kg and 42.7 L, respectively, after intravenous administrations.
Showed a high permeability, with the Papp(A→B) (19.4-63.9) × 10-6 cm/s in Caco-2 cells monolayer model.
Distribution of Tasimelteon
Exhibited moderate plasma protein binding in humans (85.8%-90.3%), mice (73.5%-77.6%), rats (76.8%-84.8%) and monkeys (69.0%-79.7%).
Rats after oral administration: [15]
● The drug was widely distributed into tissues, and had a relatively short half-life.
● Relatively higher drug concentration levels (in order) were observed in stomach, small intestine, liver, kidneys, plasma, large intestine, blood, and adrenals.
● Based on the long half-life of radioactivity in the eyes (126 h) and pigmented versus non-pigmented skin (15.4 vs. 7.6 h) following dosing of [14C]tasimelteon, binding of tasimelteon to melanin was suggested.
● The half-life of elimination of the radioactivity from brain was approximately 1 h. The tissues still showing radioactivity after 168 h were eyes, liver, thyroid, lungs, and kidneys.
Metabolism of Tasimelteon
Tasimelteon was extensively metabolized by CYP enzymes in the liver primarily by CYP1A2 and CYP3A4, and to a lesser extent by CYP1A1, CYP2D6, CYP2C19 and CYP2C9.
The major metabolic routes of tasimelteon in humans were oxidation at multiple sites and oxidative dealkylation resulting in opening of the furan ring (O-dealkylation), followed by further oxidation to give carboxylic acid. Phenolic glucuroni- dation was the major phase II metabolic route.
M9 represented the most abundant component in human plasma, with M12, M13, M9, M11 and M14 as the major metabolites. However, metabolites M12, M14 and M9 were inactive.
Total eight metabolites were identified in plasma, urine and feces of humans.
Human metabolite M11 was not detected in rats.
Excretion of Tasimelteon
Was predominantly excreted in urine of humans and monkeys, with M9 as the major significant component in human urine.
Drug-Drug Interaction
Tasimelteon and the major metabolites (M9, M12 and M13) had no direct inhibition or time-dependent inhibition of CYP enzymes evaluated (CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2D6) in vitro. Tasimelteon and M12 had weak inhibition for CYP3A4 and CYP2C19 in vitro.
Tasimelteon induced CYP2C8 (up to 60.3%) and CYP3A4 (up to 83.2%) in vitro, but tasimelteon and its metabolites (M9, M12 and M13) did not induce CYP1A2 or CYP2B6.
Tasimelteon was not a substrate of P-gp, OATP1B1 or OATP1B3.
Tasimelteon and its metabolites M9, M12 and M13 had no inhibition for OATP1B1, OATP1B3, OAT1 or OCT3, but had weak inhibition for P-gp, BCRP and OCT2 in vitro.
Update Date：2016-06-15
Single-Dose Toxicity
Single doses toxicity in rats, mice, and monkeys:
● Generally, single doses of up to 400 mg/kg in rats and mice and 200 mg/kg in monkeys were tolerated.
● Rat MNLD was considered at 1750 mg/kg, yet the testes showed CNS signs, labored respiration, and BW reductions.
● In mice, 1750 mg/kg resulted in mortality, in addition to the signs previously noted in rats at the same dose.
Repeated-Dose Toxicity
Sub- and chronic toxicity studies by the oral route in mice (up to 13 weeks), rats (up to 6 months) and monkeys (up to12 months):
● Major target organs of toxicity consistently in all species included the CNS, liver, kidney and reproductive organs. Some changes were observed in the hematologic and endocrine systems, and related organs as well.
● Exposure indicated accumulation and sex difference.
Safety Pharmacology
The core battery of safety pharmacology studies were not performed, except for in vitro and in vivo (dog) cardiovascular studies.
● CNS and respiratory effects were not studied, thereby not determinate.
● The major cardiovascular findings were reductions in BP and HR, and shortened APD in anesthetized dogs. Besides, tasimelteon seemed vasoconstrictive.
Genotoxicity
In vitro and in vivo genotoxicity on tasimelteon and M11 (a non-major human circulating metabolite that had poor coverage in the animal species):
● Tasimelteon was neither mutagenic in an Ames assay nor clastogenic in an in vivo rat micronucleus assay, however, an in vitro chromosomal aberration assay presented equivocal/positive clastogenic effects.
● Metabolite M11 was not mutagenic, but was clastogenic in an in vitro chromosomal aberration assay in CHO cells.
Reproductive and Developmental Toxicity
Fertility and early embryonic development in rats:
● Irregular estrus cycles, slightly increased infertile pairings, and slight reductions in fertility parameters were observed in females.
Embryo-fetal development in rats and rabbits:
● Slight delays in development and decreased fetal BWs were observed at MD and HD in rats and rabbits, and some maternal toxicity was observed at HD in the dams and does.
Pre and post-natal development in rats:
● Limited F0 maternal toxicity was demonstrated; Clear toxicity in the F1 generation was demonstrated particularly as developmental delays and a reduced growth rate postpartum and into adulthood, and meanwhile exposure through milk to tasimelteon, M9, M12 and M14 were identified; In the adult female F1 generation, there were some evidences for maternal toxicities and reductions in fertility at HD.
Carcinogenicity
Two-year carcinogenicity bioassays in rats and mice:
● Neoplasms in liver, uterus and cervix were drug- related in rats, yet which were not identified in mice.
