Chemical formula: C₁₅H₁₉NO₂ Molecular mass: 245.322 g/mol PubChem compound: 10220503
Tasimelteon is a circadian regulator that resets the master body clock in the suprachiasmatic nucleus (SCN). Tasimelteon acts as a Dual Melatonin Receptor Agonist (DMRA) with selective agonist activity at the MT1 and MT2 receptors. These receptors are thought to be involved in the control of circadian rhythms. The master body clock regulates the circadian rhythms of hormones including melatonin and cortisol and aligns/synchronises the physiological processes of the sleep-wake cycle and metabolic and cardiovascular homeostasis.
Tasimelteon functions as a DMRA at the MT1 and MT2 receptors. Tasimelteon exhibits a greater affinity for the MT2 as compared to the MT1 receptor. The most abundant metabolites of tasimelteon have less than one-tenth of the binding affinity of the parent molecule for both the MT1 and MT2 receptors.
Tasimelteon and its most abundant metabolites have no appreciable affinity for more than 160 other pharmacologically relevant receptors. This includes the GABA receptor complex, the binding site for sedative hypnotics, and receptors that bind neuropeptides, cytokines, serotonin, noradrenaline, acetylcholine, and opiates.
The pharmacokinetics of tasimelteon is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the recommended daily dosage). The pharmacokinetics of tasimelteon and its metabolites did not change with repeated daily dosing.
The peak concentration (Tmax) of tasimelteon occurred approximately 0.5 hours after fasted oral administration. The mean absolute oral bioavailability of tasimelteon is 38%.
When administered with a high-fat meal, the Cmax of tasimelteon was 44% lower than when administered in a fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, tasimelteon should be taken without food; if patients eat a high-fat meal, it is recommended to wait at least 2 hours before taking tasimelteon.
The apparent oral volume of distribution at steady state of tasimelteon in young healthy subjects is approximately 59 – 126 L. At therapeutic concentrations, tasimelteon is about 88.6 – 90.1% bound to proteins.
Tasimelteon is extensively metabolised. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 (35.4%) and CYP3A4 (24.3%) are the major enzymes identified to play a role in the metabolism of tasimelteon. CYP2C9 (18.8%) and CYP2C19 (15.1%) also contribute to the metabolism of tasimelteon. Tasimelteon clearance does not appear to be affected by polymorphisms in these enzymes.
Phenolic glucuronidation is the major phase II metabolic route.
Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon.
Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in faeces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.
The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours. The mean terminal elimination half-life ± standard deviation of the main metabolites ranges from 1.3 ± 0.5 to 3.7 ± 2.2.
Repeated once daily dosing with tasimelteon does not result in changes in pharmacokinetic parameters or significant accumulation of tasimelteon.
In elderly subjects, tasimelteon exposure increased by approximately two-fold compared to non-elderly adults. Due to the overall inter-subject variability of tasimelteon, this increase is not clinically meaningful and dose adjustment is not recommended.
The mean overall exposure of tasimelteon was approximately 1.6-fold greater in female than in male subjects. Due to the overall inter-subject variability of tasimelteon, this increase is not clinically meaningful and dose adjustment is not recommended.
Race does not affect apparent clearance of tasimelteon.
The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among 8 subjects with mild hepatic impairment (Child-Pugh Score ≥5 and ≤6 points), 8 subjects with moderate hepatic impairment (Child-Pugh Score ≥7 and ≤9 points), and 13 healthy matched controls. Tasimelteon exposure was increased less than two-fold in subjects with moderate hepatic impairment. Therefore, no dose adjustment is needed in patients with mild or moderate hepatic impairment. Tasimelteon has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore caution is recommended when prescribing tasimelteon to patients with severe hepatic impairment.
The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among 8 subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] ≤29 mL/min/1.73m²), 8 subjects with end-stage renal disease (ESRD) (GFR <15 mL/min/1.73m²) requiring hemodialysis, and 16 healthy matched controls. There was no apparent relationship between tasimelteon CL/F and renal function, as measured by either estimated creatinine clearance or eGFR. Subjects with severe renal impairment had a 30% lower CL/F clearance than match controls; however, when variability is taken into account, the different was not significant. No dose adjustment is necessary for patients with renal impairment.
Tasimelteon exposure decreased by approximately 40% in smokers, compared to non-smokers. The patient should be instructed to cease or reduce smoking while taking tasimelteon.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
In pregnant rats administered tasimelteon during the period of organogenesis, there were no effects on embryofoetal development. In pregnant rabbits administered tasimelteon during the period of organogenesis, embryolethality and embryofoetal toxicity (reduced foetal body weight and delayed ossification) were observed at the highest dose tested (200 mg/kg/day).
Oral administration of tasimelteon to rats throughout organogenesis and lactation resulted in persistent reductions in body weight, delayed sexual maturation and physical development, neurobehavioural impairment in offspring at the highest dose tested, andreduced body weight in offspring at the mid-dose tested. The no effect dose (50 mg/kg/day) is approximately 25 times the RHD on a mg/m² basis.
No evidence of carcinogenic potential was observed in mice; the highest dose tested is approximately 75 times the RHD of 20 mg/day, on a mg/m² basis. In rats, the incidence of liver tumours was increased in males (adenoma and carcinoma) and females (adenoma) at 100 and 250 mg/kg/day; the incidence of tumours of the uterus (endometrial adenocarcinoma) and uterus and cervix (squamous cell carcinoma) were increased at 250 mg/kg/day. There was no increase in tumours at the lowest dose tested in rats, which is approximately 10 times the recommended human doseon a mg/m² basis.
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