This will be a Phase 1, single-center, randomized, balanced, single-dose, two-period, two-sequence, crossover, open-label study to evaluate the effect of food on the pharmacokinetics of PA-824. The hypothesis to be tested in this study is that the rate and extent of absorption of two doses of PA-824 (50mg or 400 mg and 200mg) are the same after a high-calorie, high-fat meal as compared with after a minimum 10-hour fast. For each of the two dose levels 16 subjects with approximately 8 men and 8 women, will be enrolled for a total of 32 subjects.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
32
Two single administrations of 200mg PA-824 each administered by four 50mg tablets, one administered in the fed state and one administered in the fasted state. The two administrations were separated by 8 days.
Two single administrations of 50mg PA-824 each administered by one 50mg tablet, one administered in the fed state and one administered in the fasted state. The two administrations were separated by 8 days.
MDS Pharma Services (Celerion)
Lincoln, Nebraska, United States
Time of the maximum drug concentration in hours [Tmax]
To compare the rate and extent of absorption as measured by Tmax of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Tmax is obtained without interpolation.
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Maximum observed drug concentration in ng/mL [Cmax]
To compare the rate and extent of absorption as measured by Cmax of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast.
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Area under the drug concentration-time curve in ng*hr/mL [AUC(0-t)]
To compare the rate and extent of absorption as measured by AUC(0-t) of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. AUC(0-t) is calculated using linear trapezoidal summation from time zero to time t, where t is the time of the last measurable concentration.
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Area under the drug concentration-time curve from time zero to infinity in ng*hr/mL [AUC(0-inf)]
To compare the rate and extent of absorption as measured by AUC(0-inf) of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. AUC(0-inf) is calculated as AUC(0-t) + Ct/Kel.
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Ratio of AUC(0-t) to AUC(0-inf) [AUC(0-t)/ AUC(0-inf)]
To compare AUC(0-t)/ AUC(0-inf) of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast.
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Number of participants with adverse events
To compare the safety and tolerability as measured by the number of participants with adverse events after a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast.
Time frame: through the study Day 13, and through Day 103 for SAE and ophthalmologic events
Elimination half-life in hours [t1/2]
To compare t1/2 of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. T1/2 is calculated as ln (2)/Kel.
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Terminal elimination rate constant in 1/hour [Kel]
To compare Kel of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Kel is calculated by linear regression of the terminal linear portion of the log concentration vs. time curve, using at least 3 data points
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Oral clearance in L/hour [Cl/F]
To compare Cl/F of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Cl/F is calculated as Dose/AUC(0-inf).
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Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Volume of distribution following oral administration in L [Vd/F]
To compare Vd/F of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Vd/F is calculated as (CL/F)/Kel.
Time frame: mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose