A Randomized Study Investigating Oral Desmetramadol Dose Proportionality and Food Effect In Normal Human Subjects

An open-label, randomized, balanced, single-dose, four-treatment, four-period, four-sequence (using a Williams' square design) cross-over study with each dose separated by >3 days. There are 4 sequences (Sequence 1, Sequence 2, Sequence 3, and Sequence 4), and 4 Periods (Period I, Period II, Period III, and Period IV). Sequence 1 order is 30 mg dose with food (Period I); 30 mg dose fasted (Period II), 10 mg dose fasted (Period III), and 20 mg dose fasted (Period IV). Sequence 2 order is 10 mg dose fasted (Period I); 30 mg dose with food (Period II), 20 mg dose fasted (Period III), and 30 mg dose fasted (Period IV). Sequence 3 order is 20 mg dose fasted (Period I); 10 mg dose fasted (Period II), 30 mg dose fasted (Period III), and 30 mg dose with food (Period IV). Sequence 4 order is 30 mg dose fasted (Period I); 20 mg dose fasted (Period II), 30 mg dose with food (Period III), and 10 mg dose fasted (Period IV).

To account for potential dropouts, up to 32 eligible subjects will be randomized to obtain a target sample of 24 subjects with PK responses at each of the four treatment periods (based on our completed phase 1 study in 43 subjects, dropouts are unlikely (~5%); see Section 1.2.2). Before each oral dose, subjects will be fasted overnight for at least 10 hours. Treatment sequences will include the following four unblinded single-dose oral treatments: 1) desmetramadol 1 x 10 mg tablet; 2) desmetramadol 2 x 10 mg tablets; 3) desmetramadol 3 x 10 mg tablets; and 4) desmetramadol 3 x 10 mg tablets following a high-fat, high-calorie breakfast served approximately 30 minutes before dosing and entirely consumed within 20 minutes. All subjects will fast for an additional four hours after desmetramadol administration. The fed treatment should be administered the desmetramadol dose approximately 30 minutes after the start of the meal. Desmetramadol will be administered with approximately 240 ml of water. No water is allowed one hour before and one hour after each desmetramadol administration.

This will be an inpatient study. Subjects will be admitted to the clinical pharmacology unit on Study Day -1, and administered a single oral dose treatment on Study Day 1, Study Day 4, Study Day 7 and Study Day 10. After completing study procedures on Day 11 the subject will be discharged from the facility.

Blood specimens for plasma preparation and PK analysis will be collected at the following times: pre-dose (0 h), and post-dose 0.5, 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, and 32 h.

Inclusion criteria

• Healthy males and females with vital signs as follows at screening: systolic blood pressure > 90 mm Hg and < 140 mm Hg; diastolic blood pressure > 40 mm Hg and < 90 mm Hg; pulse 40 to 99 beats per minute; respiratory rate 12 to 24 breathes per minute.
• Age 19 to 55 years.
• Able and willing to give informed consent
• Able to comply with all study procedures.
• If female, must not be of childbearing potential or must agree to use one or more of the following forms of contraception from screening, throughout the study and for 30 days following study drug administration: hormonal (e.g., oral, transdermal, intravaginal, implant or injection for 3 months); double barrier (e.g., condom or diaphragm with spermicide); intrauterine device (IUD) or system (IUS) (for 3 months); vasectomized partner (6 months minimum); or abstinence.

Screening laboratory results must be within normal range per clinical research unit: serum sodium, potassium, calcium, BUN, creatinine, ALT, AST, total bilirubin, alkaline phosphatase, glucose (random), albumin, total protein, WBC and differential, hemoglobin, and platelets. In addition PT and PTT must be < 1.2 ULN.

• Electrocardiogram (ECG) without clinically significant abnormalities.

Urinalysis demonstrating < +1 glucose, and +1 protein.

• If female, must have a negative pregnancy test at screening
• Negative urine test for substances of abuse, including opiates, per clinical pharmacology unit standards at screening and clinic check-in.
• Negative serology tests for HIV, hepatitis B surface antigen, and hepatitis C virus antibody.
• Weight > 50 Kg and a body mass index (BMI) of 18.0 to 32.0 kg/m (inclusive).
• Non-smoker of tobacco for a minimum of the past 3 months, and negative urine continine test.

Exclusion criteria

• Oral temperature > 38°C or current illness.
• History of seizures, epilepsy, or recognized increase risk of seizure (e.g., head trauma, metabolic disorders, alcohol or drug withdrawal).
• History of cirrhosis or laboratory evidence of liver disease.
• Having undergone gall bladder removal.
• Use of alcohol within 24 hours of day -1 until the end of the study; and grapefruit, grapefruit-related citrus fruits (e.g., Seville oranges, pomelos), or grapefruit juice or grapefruit-related juices within 7 days of study drug administration and until the end of the study.
• History of previous anaphylaxis, severe allergic reaction to tramadol, codeine, or other opioid drugs.
• Any other unstable acute or chronic disease that could interfere with the evaluation of the safety of the study drug as determined by the principal Investigator in dialogue with the Sponsor Medical Monitor.
• Females must not be currently pregnant or breast feeding.
• Unlikely to comply with the study protocol.
• Known or suspected alcohol or drug abuse within the past 6 months.
• Received another investigational agent within 4 weeks of Day -1, or within five half-lives of Day -1, whichever is longer; or receiving any other investigational agent during this study.
• Any concurrent disease or condition that in the opinion of the investigator impairs the subject's ability to complete the trial. Psychological, familial, sociological, geographical or medical conditions which, in the Investigator's opinion, could compromise compliance with the objectives and procedures of this protocol, or obscure interpretation of the trial data.