Tasimelteon

The mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 is unclear. However, tasimelteon is an agonist at melatonin MT₁ and MT₂ receptors which are thought to be involved in the control of circadian rhythms.

Tasimelteon is an agonist at MT₁ and MT₂ receptors with greater affinity for the MT₂ as compared to the MT₁ receptor (Ki = 0.304 nM and 0.07 nM, respectively). The major metabolites of tasimelteon have less than one-tenth of the binding affinity of the parent molecule for both the MT₁ and MT₂ receptors.

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.

Absorption

The absolute oral bioavailability is 38.3%. The peak concentration (T_max) of tasimelteon occurred approximately 0.5 to 3 hours after fasted oral administration.

When administered with a high-fat meal, the C_max of tasimelteon was 44% lower than when given in a fasted state, and the median T_max was delayed by approximately 1.75 hours. Therefore, tasimelteon should be taken without food.

Distribution

The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 59-126 L. At therapeutic concentrations, tasimelteon is about 90% bound to proteins.

Metabolism

Tasimelteon is extensively metabolized. 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 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon.

Phenolic glucuronidation is the major phase II metabolic route.

Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon.

Elimination

Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, 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.

Studies in Specific Populations

Elderly

In elderly subjects, tasimelteon exposure increased by approximately two-fold compared with non-elderly adults.

Gender

The mean overall exposure of tasimelteon was approximately 20-30% greater in female than in male subjects.

Race

The effect of race on exposure of tasimelteon was not evaluated.

Hepatic Impairment

The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among eight subjects with mild hepatic impairment (Child-Pugh Score ≥5 and ≤6 points), eight 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) and is not recommended in these patients.

Renal Impairment

The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] ≤29 mL/min/1.73m²), eight subjects with end-stage renal disease (ESRD) (GFR <15 mL/min/1.73m²) requiring hemodialysis, and sixteen 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 clearance, and clearance in subjects with ESRD was comparable to that of healthy subjects. No dose adjustment is necessary for patients with renal impairment.

Smokers (smoking is a moderate CYP1A2 inducer)

Tasimelteon exposure decreased by approximately 40% in smokers, compared to non- smokers.

Drug Interaction Studies

No potential drug interactions were identified in in vitro studies with CYP inducers or inhibitors of CYP1A1, CYP1A2, CYP2B6, CYP2C9/2C19, CYP2E1, CYP2D6, and transporters including P-glycoprotein, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3.

Effect of Other Drugs on Tasimelteon

Drugs that inhibit CYP1A2 and CYP3A4 are expected to alter the metabolism of tasimelteon:

• Fluvoxamine (strong CYP1A2 inhibitor): the AUC_0-inf and C_max of tasimelteon increased by 7-fold and 2-fold, respectively, when co-administered with fluvoxamine 50 mg (after 6 days of fluvoxamine 50 mg per day).
• Ketoconazole (strong CYP3A4 inhibitor): tasimelteon exposure increased by approximately 50% when co-administered with ketoconazole 400 mg (after 5 days of ketoconazole 400 mg per day).
• Rifampin (strong CYP3A4 and moderate CYP2C19 inducer): the exposure of tasimelteon decreased by approximately 90% when co-administered with rifampin 600 mg (after 11 days of rifampin 600 mg per day). Efficacy may be reduced when tasimelteon is used in combination with strong CYP3A4 inducers, such as rifampin.

Effect of Tasimelteon on Other Drugs

• Midazolam (CYP3A4 substrate): Administration of tasimelteon 20 mg once a day for 14 days did not produce any significant changes in the T_max, C_max, or AUC of midazolam or 1-OH midazolam. This indicates there is no induction of CYP3A4 by tasimelteon at this dose.
• Rosiglitazone (CYP2C8 substrate): Administration of tasimelteon 20 mg once a day for 16 days did not produce any clinically significant changes in the T_max, C_max, or AUC of rosiglitazone after oral administration of 4 mg. This indicates that there is no induction of CYP2C8 by tasimelteon at this dose.

Effect of Alcohol on Tasimelteon

In a study of 28 healthy volunteers, a single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was co-administered with a 20 mg dose of tasimelteon. There was a trend for an additive effect of tasimelteon and ethanol on some psychomotor tests.