Safety, Tolerability, Pharmacokinetics And Measurement Of Whole Blood Activity (WBA) Of PNU-100480 After Multiple Oral Doses In Healthy Adult Volunteers

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety, tolerability and pharmacokinetics of multiple doses of PNU-100480 given for 14 or 28 days. Killing activity against the bacterium that causes tuberculosis (TB) will also be measured. The effect of adding an additional tuberculosis (TB) agent (given for 2 days) in addition to PNU-100480 will be evaluated. Linezolid open label to determine activity in whole blood assay (WBA).

Detailed Description
-----------------
Evaluate safety, tolerability, pharmacokinetics and whole blood activity (WBA) of PNU-100480 given for 14 or 28 days; evaluate WBA of PNU with pyrazinamide; evaluate WBA of linezolid

Official Title
-----------------
A Phase 1, Double-Blind, Randomized, Placebo-Controlled Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of PNU-100480 (PF-02341272) After Administration Of Multiple Escalating Oral Doses To Healthy Adult Subjects

Conditions
-----------------
Tuberculosis

Intervention / Treatment
-----------------
* Drug: PNU-100480
* Drug: Placebo
* Drug: PNU-100480
* Drug: Placebo
* Drug: PNU-100480
* Drug: Placebo
* Drug: PNU-100480
* Drug: Placebo
* Drug: PNU-100480
* Drug: Placebo
* Drug: PNU-100480
* Drug: Placebo
* Drug: Linezolid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adult volunteers willing and able to be confined to the Clinical Research Unit and comply with study schedule. Women of non-childbearing potential only. Exclusion Criteria: History of hypersensitivity to, or intolerance of, linezolid. Antibiotic treatment within 14 days prior to dosing, or any previous antibiotic use at the discretion of the investigator. Previous history of irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br> | Drug: PNU-100480<br>* 100 mg BID for 14 days<br>Drug: Placebo<br>* to match 100 mg BID for 14 days<br>|
| Experimental: Cohort 2<br> | Drug: PNU-100480<br>* 300 mg BID for 14 days<br>Drug: Placebo<br>* to match 300 mg BID for 14 days<br>|
| Experimental: Cohort 3<br> | Drug: PNU-100480<br>* 600 mg BID for 14 days<br>Drug: Placebo<br>* to match 600 mg BID for 14 days<br>|
| Experimental: Cohort 4<br> | Drug: PNU-100480<br>* 1200 mg QD for 14 days<br>Drug: Placebo<br>* to match 1200 mg QD for 14 days<br>|
| Experimental: Cohort 5<br> | Drug: PNU-100480<br>* 600 mg BID for 28 days with pyrazinamide (25 mg/kg up to 2 g) QD on Days 27-28<br>Drug: Placebo<br>* placebo to match 600 mg BID for 28 days with pyrazinamide (25 mg/kg up to 2 g) QD on Days 27-28<br>|
| Experimental: Cohort 6 (optional)<br> | Drug: PNU-100480<br>* PNU-100480 dose up to total of 1200 mg daily for 28 days with pyrazinamide (25 mg/kg up to 2 g) QD on Days 27-28<br>Drug: Placebo<br>* placebo to match dose up to total of 1200 mg daily for 28 days with pyrazinamide (25 mg/kg up to 2 g) QD on Days 27-28<br>|
| Experimental: Linezolid Cohort<br> | Drug: Linezolid<br>* 300 mg QD for 4 days (open label)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of ascending oral doses of PNU-100480 administered as extemporaneously prepared suspension (EPS) over 14 and 28 days in healthy adult volunteers. |  | Monitor adverse events daily; safety eval pre-dose, specified times , discharge, follow-up/as needed | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the single dose and steady state pharmacokinetics of ascending oral doses of PNU-100480 administered over 14 and 28 days in healthy adult volunteers with regard to the parent drug and its metabolites. |  | Full and sparse PK sampling from Day 1 through final day of dosing | 
| To characterize the bactericidal activity in blood of orally administered PNU-100480 against intracellular M. tuberculosis in relation to blood concentrations ofPNU-100480 and its metabolites. |  | Full and sparse sampling from Day 1 through final day of dosing | 
| To characterize the effect of once a day administration of pyrazinamide for 2 days on the pharmacokinetics and bactericidal activity in blood of orally administered PNU-100480 against intracellular M. tuberculosis (Cohorts 5 and 6, Days 27-28 only). |  | Days 27-28 as applicable | 
| To characterize pharmacokinetics and bactericidal activity in blood of orally administered linezolid against intracellular M. tuberculosis following 4 days of QD dosing. |  | As applicable up to Day 4 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Safety tolerability pharmacokinetics (PK) pharmacodynamics whole blood activity (WBA) PNU-100480 linezolid pyrazinamide multiple dose