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).
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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Masking
DOUBLE
Enrollment
59
100 mg BID for 14 days
to match 100 mg BID for 14 days
300 mg BID for 14 days
Pfizer Investigational Site
New Haven, Connecticut, United States
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.
Time frame: Monitor adverse events daily; safety eval pre-dose, specified times , discharge, follow-up/as needed
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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: As applicable up to Day 4
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to match 300 mg BID for 14 days
600 mg BID for 14 days
to match 600 mg BID for 14 days
1200 mg QD for 14 days
to match 1200 mg QD for 14 days
600 mg BID for 28 days with pyrazinamide (25 mg/kg up to 2 g) QD on Days 27-28
placebo to match 600 mg BID for 28 days with pyrazinamide (25 mg/kg up to 2 g) QD on Days 27-28
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
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
300 mg QD for 4 days (open label)