Ascending Dose Pharmacokinetic (PK) and Absolute Bioavailability (BA)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of single rising and multiple rising IV doses of TR-701 FA and to determine the absolute bioavailability of oral TR-701 FA following single oral and IV dose administrations in healthy adult subjects.

Detailed Description
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SAD/Part A. All subjects in the Pilot Cohort will receive a single infusion of 50 mg TR-701 FA for injection in 250 cc of saline over 180 minutes. Subjects in Cohort 1 will be randomized to receive a single infusion of placebo or 100 mg of TR-701 FA for injection in 250 or 500 cc of saline over 60 or 120 minutes. Subjects in Cohort 2 will be randomized to receive a single infusion of placebo or 200 mg of TR-701 FA for injection in 250 or 500 cc of saline over 60 or 120 minutes. Subjects in Cohort 3 will be randomized to receive a single infusion of placebo or 400 mg of TR-701 FA for injection in 250 or 500 cc of saline over 60 or 120 minutes. MAD/Part B Subjects in Cohort 4 will be randomized to receive once daily infusions of placebo or 200 mg of TR-701 FA for injection in 250 cc of saline over 60 minutes for 7 days. Subjects in Cohort 5 will be randomized to receive once daily infusions of placebo or 300 mg of TR-701 FA for injection in 250 cc of saline over 60 minutes for 7 days. BA/Part C Subjects in Cohort 6 will receive a single 60 minute infusion of 200 mg TR-701 FA for injection in 250 cc of saline and a singe oral dose of 200 mg TR-701 FA tablet in an open-label crossover design. Venous Tolerability/Part D - Subjects in Cohort 8 will receive once daily 60 minute infusions of 200 mg TR-701 FA for injection in 250 cc of saline for 3 days and once daily placebo infusions for 3 daysin a blinded crossover design.

Official Title
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A Double-Blind, Placebo-Controlled, Single & Multiple Ascending Dose, Safety, Tolerability, & PK Study of an IV Form of TR-701 Free Acid & an Open-Label, Crossover Absolute BA Determination of a TR-701 FA Tablet in Normal Healthy Adults

Conditions
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Bacterial Infections

Intervention / Treatment
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* Drug: TR-701 FA for injection, 200 mg/vial
* Drug: TR-701 FA tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: in good health body mass index of 20 to 29.9 kg/m2 female subjects must be post menopausal for at least 1 year, surgically sterile, abstinent or agree to use an effective method of birth control Exclusion Criteria: history or clinical manifestation of any clinically significant disorder history of hypersensitivity to any drug compound history of stomach or intestinal surgery or resection history of infections of unexplained frequency or severity history of alcoholism or drug addiction within 1 year use of any tobacco- or nicotine-containing products within 6 months use of alcohol-, grapefruit-, caffeine-, or high tyramine-containing foods or beverages use of any other medications pregnancy, lactation, or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD/ Part A<br>Single IV infusions of placebo or TR-701 FA given at 50, 100, 200, and 400 mg. | Drug: TR-701 FA for injection, 200 mg/vial<br>* TR-701 FA for injection will be given as a single infusion at doses of 50 mg, 100 mg, 200 mg, and 400 mg in SAD/Part A (Pilot and Cohorts 1 to 3). TR-701 FA for injection will be given as once daily infusions at doses of 200 mg and 400 mg for 7 days in MAD/Part B (Cohorts 4 & 5). TR-701 FA for injection will be given once as a 200 mg IV infusion in BA/Part C (Cohort 6). TR-701 FA 200 mg will be given daily for 3 days in Venous Tolerability/Part D<br>* Other names: Torezolid Phospate;|
| Experimental: MAD / Part B<br>Multiple IV infusion of placebo or TR-701 FA given daily for 7 days at 200 and 400 mg. | Drug: TR-701 FA for injection, 200 mg/vial<br>* TR-701 FA for injection will be given as a single infusion at doses of 50 mg, 100 mg, 200 mg, and 400 mg in SAD/Part A (Pilot and Cohorts 1 to 3). TR-701 FA for injection will be given as once daily infusions at doses of 200 mg and 400 mg for 7 days in MAD/Part B (Cohorts 4 & 5). TR-701 FA for injection will be given once as a 200 mg IV infusion in BA/Part C (Cohort 6). TR-701 FA 200 mg will be given daily for 3 days in Venous Tolerability/Part D<br>* Other names: Torezolid Phospate;|
| Experimental: Bioavailability / Part C<br>TR-701 FA tablet given once orally as a 200 mg tablet or TR-701 FA for injection given once as a 200 mg IV infusion. | Drug: TR-701 FA for injection, 200 mg/vial<br>* TR-701 FA for injection will be given as a single infusion at doses of 50 mg, 100 mg, 200 mg, and 400 mg in SAD/Part A (Pilot and Cohorts 1 to 3). TR-701 FA for injection will be given as once daily infusions at doses of 200 mg and 400 mg for 7 days in MAD/Part B (Cohorts 4 & 5). TR-701 FA for injection will be given once as a 200 mg IV infusion in BA/Part C (Cohort 6). TR-701 FA 200 mg will be given daily for 3 days in Venous Tolerability/Part D<br>* Other names: Torezolid Phospate;Drug: TR-701 FA tablets<br>* TR-701 FA will be given once orally as a 200 mg tablet in Part C.<br>* Other names: Torezolid Phosphate Tablet;|
| Experimental: Venous Tolerability/ Part D<br>IV infusions of placebo and 200 mg TR-701 FA given daily for 3 days, | Drug: TR-701 FA for injection, 200 mg/vial<br>* TR-701 FA for injection will be given as a single infusion at doses of 50 mg, 100 mg, 200 mg, and 400 mg in SAD/Part A (Pilot and Cohorts 1 to 3). TR-701 FA for injection will be given as once daily infusions at doses of 200 mg and 400 mg for 7 days in MAD/Part B (Cohorts 4 & 5). TR-701 FA for injection will be given once as a 200 mg IV infusion in BA/Part C (Cohort 6). TR-701 FA 200 mg will be given daily for 3 days in Venous Tolerability/Part D<br>* Other names: Torezolid Phospate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Assessments |  | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the pharmacokinetics of TR-701 and its microbiologically active moiety TR-700 after single and multiple IV doses of TR-701 FA |  | 10 days | 
| To determine the absolute bioavailability of oral TR-701 FA following single oral and IV dose administrations in healthy adult subjects |  | 4 days |