Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%.

Absolute Bioavailability of Tasimelteon.

Tasimelteon is a novel dual melatonin receptor agonist and is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. This study was conducted to assess the absolute bioavailability of tasimelteon and to further assess the single-dose pharmacokinetics, safety, and tolerability of oral and intravenous (IV) routes of administration of the drug. This study was an open-label, single-dose, randomized, 2-period, 2-treatment, 2-sequence, crossover study in which 14 healthy volunteers were randomly administered tasimelteon as either a 20-mg capsule or IV administration of 2 mg infused over 30 minutes. Each subject received both treatments in a random order, separated by a washout period of 5 ± 2 days. The total clearance and volume of distribution of tasimelteon, from the IV treatment, were 505 mL per minute and 42.7 L, respectively. Based on the statistical comparison of dose-corrected area under the curve to infinity, the absolute bioavailability was 38%, with a 90% confidence interval of 27%-54%. The mean elimination half-life was the same for the oral and IV routes. The exposure ratios, oral-to-IV, for metabolites M9, M11, M12, and M13, were 133.27%, 118.28%, 138.76%, and 112.36%, respectively, suggesting presystemic or first-pass metabolism. Three (21.4%) subjects experienced a treatment-emergent adverse event (TEAE) during the study. All TEAEs were mild, considered related to study medication, and consistent with what has been seen in other studies. There were no deaths, serious adverse events, or discontinuations due to TEAEs. Both tasimelteon treatments were well tolerated during the study.

Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment.

Tasimelteon is a circadian regulator that resets the master clock in the suprachiasmatic nuclei of the hypothalamus by binding to both melatonin MT1 and MT2 receptors making it a dual melatonin receptor agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open-label studies evaluated the pharmacokinetics of tasimelteon and its main metabolites after a single 20 mg dose administered to subjects with mild or moderate hepatic impairment or severe renal impairment, including subjects on dialysis compared to healthy controls. In subjects with mild or moderate hepatic impairment, exposure to tasimelteon after a single 20 mg dose, as measured by area under the plasma concentration-time curve to infinity, was increased by approximately 2-fold. There was no apparent relationship between tasimelteon clearance and renal function. No safety concerns were apparent in either study. Based on these results, the changes in the pharmacokinetics of tasimelteon due to mild or moderate hepatic or severe renal impairment are not considered clinically relevant, and no dose adjustment is necessary in these patients.

A phase 2a randomized, parallel group, dose-ranging study of molindone in children with attention-deficit/hyperactivity disorder and persistent, serious conduct problems.

OBJECTIVE: To evaluate safety and tolerability of four doses of immediate-release molindone hydrochloride in children with attention-deficit/hyperactivity disorder (ADHD) and serious conduct problems. METHODS: This open-label, parallel-group, dose-ranging, multicenter trial randomized children, aged 6-12 years, with ADHD and persistent, serious conduct problems to receive oral molindone thrice daily for 9-12 weeks in four treatment groups: Group 1-10 mg (5 mg if weight <30 kg), group 2-20 mg (10 mg if <30 kg), group 3-30 mg (15 mg if <30 kg), and group 4-40 mg (20 mg if <30 kg). The primary outcome measure was to evaluate safety and tolerability of molindone in children with ADHD and serious conduct problems. Secondary outcome measures included change in Nisonger Child Behavior Rating Form-Typical Intelligence Quotient (NCBRF-TIQ) Conduct Problem subscale scores, change in Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) subscale scores from baseline to end point, and Swanson, Nolan, and Pelham rating scale-revised (SNAP-IV) ADHD-related subscale scores. RESULTS: The study randomized 78 children; 55 completed the study. Treatment with molindone was generally well tolerated, with no clinically meaningful changes in laboratory or physical examination findings. The most common treatment-related adverse events (AEs) included somnolence (n=9), weight increase (n=8), akathisia (n=4), sedation (n=4), and abdominal pain (n=4). Mean weight increased by 0.54 kg, and mean body mass index by 0.24 kg/m(2). The incidence of AEs and treatment-related AEs increased with increasing dose. NCBRF-TIQ subscale scores improved in all four treatment groups, with 34%, 34%, 32%, and 55% decreases from baseline in groups 1, 2, 3, and 4, respectively. CGI-S and SNAP-IV scores improved over time in all treatment groups, and CGI-I scores improved to the greatest degree in group 4. CONCLUSIONS: Molindone at doses of 5-20 mg/day (children weighing <30 kg) and 20-40 mg (≥ 30 kg) was well tolerated, and preliminary efficacy results suggest that molindone produces dose-related behavioral improvements over 9-12 weeks. Additional double-blind, placebo-controlled trials are needed to further investigate molindone in this pediatric population.