Comparative Bioavailability of Sublingual TNX-102, Oral and Intravenous Cyclobenzaprine in Healthy Adults

Study Overview
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Brief Summary
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Very low dose (VLD) cyclobenzaprine at bedtime has shown promise as a treatment for fibromyalgia, but the chemistry of cyclobenzaprine requires new formulation technology for bedtime use. The present trial is designed to assess the safety and tolerability of sublingual TNX-102 2.4 mg (a new formulation of cyclobenzaprine designed to result in increased dosage precision and decreased potential for morning grogginess) at pH 3.5 and 7.1 and to compare the bio-availability of sublingual TNX-102 2.4 mg at pH 3.5 and 7.1 and cyclobenzaprine (5 mg tablets, or 2.4 mg iv).

Official Title
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A Single-Dose, Open-Label, Randomized Study of the Comparative Pharmacokinetics of Sublingual TNX-102 2.4 mg at pH 3.5 and 7.1, Oral Cyclobenzaprine 5 mg Tablets, and Intravenous Cyclobenzaprine 2.4 mg in Healthy Adults

Conditions
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Healthy Adults

Intervention / Treatment
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* Drug: SL TNX-102 2.4 mg at pH 3.5
* Drug: SL TNX-102 2.4 mg at pH 7.1
* Drug: Cyclobenzaprine Tablet
* Drug: Cyclobenzaprine IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults Male or female Non-smoker 18-65 years old BMI > 18.5 and < 30.0 With medically acceptable form of contraception (female only) With signed informed consent Exclusion Criteria: Any clinically significant abnormality including ECG abnormalities or vital sign abnormalities (systolic blood pressure < 90 or > 140 mmHg, diastolic blood pressure lower < 50 or > 90 mmHg, or heart rate < 50 or > 100 BPM) Any abnormal laboratory test (including positivity for Hep B, Hep C, HIV, and Hemoglobin < 128 g/L (males) or < 115 g/L (females) and hematocrit < 0.37 L/L (males) or < 0.32 L/L (females)) History of alcohol or drug abuse or dependence within 1 year and/or positive drug, cotinine, or alcohol tests Use of any drug (within 30 days), supplement, or food (within 14 days) known to induce or inhibit hepatic drug metabolism prior to study medication Positive pregnancy test, breastfeeding or lactating Use of medication other than hormonal contraceptives or topical products, including OTC, natural health products, MAO inhibitors Participation in an investigational study within 30 days prior to dosing Donation of plasma (within 7 days), or donation or loss of blood of 50-499 mL (within30 days), or of > 499 mL (within 56 days) prior to dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SL TNX-102 at pH 3.5<br>2.4 mg TNX-102 sublingual solution (2.4 mg/mL) in PBS at pH 3.5 | Drug: SL TNX-102 2.4 mg at pH 3.5<br>* 1 dose of 2.4 mg TNX-102 sublingual solution (2.4 mg/mL) in PBS at pH 3.5, administered as 1 mL held under the tongue for 90 seconds without swallowing<br>|
| Experimental: SL TNX-102 at pH 7.1<br>2.4 mg TNX-102 sublingual solution (2.4 mg/mL) in PBS at pH 7.1 | Drug: SL TNX-102 2.4 mg at pH 7.1<br>* 1 dose of 2.4 mg TNX-102 sublingual solution (2.4 mg/mL) in PBS at pH 7.1, administered as 1 mL held under the tongue for 90 seconds without swallowing<br>|
| Active Comparator: Cyclobenzaprine tablets<br>5 mg cyclobenzaprine tablet once | Drug: Cyclobenzaprine Tablet<br>* 1 x 5 mg cyclobenzaprine tablet, swallowed with 240 mL of room-temperature water<br>|
| Active Comparator: Cyclobenzaprine IV<br>2.4 mg cyclobenzaprine USP in PBS (0.6 mg/mL) at pH 7.4 | Drug: Cyclobenzaprine IV<br>* 1 dose of 2.4 mg cyclobenzaprine USP in PBS (0.6 mg/mL) at pH 7.4, administered intravenously as a 4 mL bolus injection over 30 seconds<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Measured levels of cyclobenzaprine and norcyclobenzaprine in plasma and urine | Blood samples will be taken per period: within 30 minutes pre-dose and 2, 3.5, 5, 10, 20, 30, and 45 minutes and 1, 2, 2.5, 3, 3.33, 3.67, 4, 4.33, 4.67, 5, 5.5, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose. A single urine sample will be collected within 30 minutes pre-dose (one sample), and urine will be pooled from 0-24, 24-48 and 48-72 hours post-dose. | 27 time points per period for blood assessment ; 3 pooled analyses in urine. | 
| Safety and tolerability of sublingual TNX-102 2.4 mg at pH 3.5 and pH 7.1. | Every adverse events occurring during the study period will be reported. | Continuously until the end (day 4) of the study period + Telephone follow-up 7-13 days after dosing (total duration: about 1 month) |