Pharmacokinetics of Tasimelteon in Subjects With Mild or Moderate Hepatic Impairment

The study will employ an open-label, parallel-group design. Up to 32 subjects will be enrolled in 3 groups: Group 1 will consist of 8 subjects with mild hepatic impairment; Group 2 will consist of 8 subjects with moderate hepatic impairment; Group 3 will consist of up to 16 healthy subjects matched by gender, age, smoking status, and body mass index, to Groups 1 and/or 2. For each group, there will be a 21-day screening period, a baseline period, a single-dose treatment period with an on-site observation period of 36 hours, and a study completion evaluation conducted after the last PK blood sample is drawn. Each subject will receive a single 20-mg dose of tasimelteon, after which safety assessments will be performed.

Inclusion criteria

All Subjects:

• Ability and acceptance to provide written informed consent;
• Men or women between 18 - 75 years, inclusive;
• Subjects with Body Mass Index (BMI) of >18 and <35 kg/m2;
• Women of child-bearing potential must be using an acceptable method of birth control;
• Willing and able to comply with study requirements and restrictions;

Subjects with mild or moderate hepatic impairment:

• Stable hepatic impairment satisfying the criteria for Class A or B of the modified Child-Pugh classification documented by medical history;
• Subjects with Moderate hepatic impairment must also have either liver cirrhosis or physical signs consistent with a clinical diagnosis of liver cirrhosis
• Creatinine clearance greater than 50 mL/min

Healthy matched controls:

• Matched to subjects with hepatic impairment by gender, age, BMI, and smoking status
• Good health as determined by past medical history, physical examination, electrocardiogram, laboratory tests, vital signs and urinalysis;

Exclusion criteria

• Smokers unable or unwilling to limit consumption;
• Exposure to any investigational drug, including placebo, within 30 days of dosing;
• Blood Donation or loss of 400 mL or more within two months prior to dosing;
• Significant illness within the two weeks prior to dosing;
• History of autonomic dysfunction;
• History of acute or chronic bronchospastic disease, including asthma and chronic obstructive pulmonary disease, treated or not treated;
• A known hypersensitivity to tasimelteon or drugs similar to tasimelteon including melatonin;
• Pregnant or lactating females;
• History of drug or alcohol abuse within the 12 months prior to screening
• History of immunocompromise, including a positive HIV (ELISA and Western blot) test result;
• Any surgical or medical condition which might significantly alter the absorption, distribution or excretion of any drug;
• Clinically significant ECG abnormalities or vital sign abnormalities at screening or a history of unstable, severe, or clinically significant cardiovascular disease;

Subjects with mild or moderate hepatic impairment:

• Clinically significant abnormal findings, not consistent with clinical disease, upon physical examination, ECG, or laboratory evaluation;
• Current symptoms or past history (within the last 6 months) of encephalopathy;
• Severe ascites;
• Previous surgical porto-systemic shunt including transjugular intrahepatic portosystemic shunt (TIPS);
• Progressive liver disease within 4 weeks prior to screening.

Healthy matched controls:

• Use of any prescription medication within 1 month of dosing, and OTC medication within 14 days prior to dosing;
• History or presence of liver disease or liver injury;
• A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.