Mechanism Of Action
The precise mechanism by which tasimelteon exerts its
therapeutic effect in patients with Non24 is not known. Tasimelteon is an
agonist at melatonin MT1 and MT2 receptors. These receptors are thought to be
involved in the control of circadian rhythms.
HETLIOZ is an agonist at MT1 and MT2 receptors. HETLIOZ
exhibits a greater affinity for the MT2 as compared to the MT1 receptor. The
most abundant metabolites of HETLIOZ have less than one-tenth of the binding
affinity of the parent molecule for both the MT1 and MT2 receptors.
The pharmacokinetics of HETLIOZ is linear over doses
ranging from 3 to 300 mg (0.15 to 15 times the recommended daily dosage). The
pharmacokinetics of HETLIOZ and its metabolites did not change with repeated
The absolute oral bioavailability is 38.3%. The peak
concentration (Tmax) of tasimelteon occurred approximately 0.5 to 3 hours after
fasted oral administration.
When administered with a high-fat meal, the Cmax of
tasimelteon was 44% lower than when given in a fasted state, and the median Tmax
was delayed by approximately 1.75 hours. Therefore, HETLIOZ should be taken
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.
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
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 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 HETLIOZ does not result
in changes in pharmacokinetic parameters or significant accumulation of
Studies in Specific Populations
In elderly subjects, tasimelteon exposure increased by
approximately two-fold compared with non-elderly adults.
The mean overall exposure of tasimelteon was
approximately 20-30% greater in female than in male subjects.
The effect of race on exposure of HETLIOZ was not
The pharmacokinetic profile of a 20 mg dose of HETLIOZ
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. HETLIOZ has not been studied
in patients with severe hepatic impairment (Child-Pugh Class C) and is not
recommended in these patients.
The pharmacokinetic profile of a 20 mg dose of HETLIOZ
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 [see Use in Specific Populations] .
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 HETLIOZ
Drugs that inhibit CYP1A2 and CYP3A4 are expected to
alter the metabolism of tasimelteon.
Fluvoxamine (strong CYP1A2 inhibitor): the AUC0-inf
and Cmax 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) [see DRUG INTERACTIONS] .
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) [see DRUG INTERACTIONS].
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 HETLIOZ is used in combination with strong CYP3A4 inducers,
such as rifampin [see DRUG INTERACTIONS] .
Effect of HETLIOZ on Other Drugs
Midazolam (CYP3A4 substrate): Administration of
HETLIOZ 20 mg once a day for 14 days did not produce any significant changes in
the Tmax, Cmax, 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 HETLIOZ 20 mg once a day for 16 days did not produce any clinically
significant changes in the Tmax, Cmax, 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 HETLIOZ
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 HETLIOZ. There was a trend for an additive effect of HETLIOZ and
ethanol on some psychomotor tests.
The effectiveness of HETLIOZ in the treatment of
Non-24-Hour Sleep-Wake Disorder (Non-24) was established in two randomized
double-masked, placebo-controlled, multicenter, parallel-group studies (Studies
1 and 2) in totally blind patients with Non-24.
In study 1, 84 patients with Non-24 (median age 54 years)
were randomized to receive HETLIOZ 20 mg or placebo, one hour prior to bedtime,
at the same time every night for up to 6 months.
Study 2 was a randomized withdrawal trial in 20 patients
with Non-24 (median age 55 years) that was designed to evaluate the maintenance
of efficacy of HETLIOZ after 12-weeks. Patients were treated for approximately
12 weeks with HETLIOZ 20 mg one hour prior to bedtime, at the same time every
night. Patients in whom the calculated time of peak melatonin level (melatonin
acrophase) occurred at approximately the same time of day (in contrast to the
expected daily delay) during the run-in phase were randomized to receive
placebo or continue treatment with HETLIOZ 20 mg for 8 weeks.
Study 1 and Study 2 evaluated the duration and timing of
nighttime sleep and daytime naps via patient-recorded diaries. During Study 1,
patient diaries were recorded for an average of 88 days during screening, and
133 days during randomization. During Study 2, patient diaries were recorded
for an average of 57 days during the run-in phase, and 59 days during the
Because symptoms of nighttime sleep disruption and
daytime sleepiness are cyclical in patients with Non-24, with severity varying
according to the state of alignment of the individual patient's circadian
rhythm with the 24-hour day (least severe when fully aligned, most severe when
12 hours out of alignment), efficacy endpoints for nighttime total sleep time
and daytime nap duration were based on the 25% of nights with the least
nighttime sleep, and the 25% of days with the most daytime nap time. In Study
1, patients in the HETLIOZ group had, at baseline, an average 195 minutes of
nighttime sleep and 137 minutes of daytime nap time on the 25% of most symptomatic
nights and days, respectively. Treatment with HETLIOZ resulted in a significant
improvement, compared with placebo, for both of these endpoints in Study 1 and
Study 2 (see Table 2).
Table 2: Effects of HETLIOZ 20 MG on Nighttime Sleep
Time and Daytime Nap Time in Study 1 and Study 2
|Change from Baseline
|HETLIOZ 20 MG
|HETLIOZ 20 MG
|Nighttime sleep time on 25% most symptomatic nights (minutes)
|Daytime nap time on 25% most symptomatic days (minutes)
A responder analysis of
patients with both ≥ 45 minutes increase in nighttime sleep and ≥
45 minutes decrease in daytime nap time was conducted in Study 1: 29% (n=12) of
patients treated with HETLIOZ, compared with 12% (n=5) of patients treated with
placebo met the responder criteria.
The efficacy of HETLIOZ in
treating Non-24 may be reduced in subjects with concomitant administration of
beta adrenergic receptor antagonists.