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Food Effect Study on the Bioavailability and PK of PA-824 Tablets in Healthy Adult Subjects (CL-003)

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ClinicalTrials.gov Identifier: NCT01828827
Recruitment Status : Completed
First Posted : April 11, 2013
Last Update Posted : January 14, 2016
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Brief Summary:
This is a Phase 1, single-center, randomized, balanced, single-dose, two-treatment, two-period, two-sequence, crossover, open-label study to evaluate the effect of food on the pharmacokinetics of PA-824. This study was designed to understand the possible effects of a high-calorie, high-fat meal on PA-824 absorption and pharmacokinetics. The hypothesis to be tested in this study is that the rate and extent of absorption of PA-824, as measured by Tmax, Cmax, AUC(0-t), and AUC(0 inf), are the same after a high-calorie, high-fat meal as compared with after a minimum 10-hour fast.

Condition or disease Intervention/treatment Phase
Tuberculosis Drug: PA-824 1000 mg Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Randomized, Balanced, Single-Dose, Two-Treatment, Two-Period, Two-Sequence, Crossover, Open-Label Study of the Effect of Food on the Bioavailability and Pharmacokinetics of PA-824 Tablets in Healthy Adult Subjects
Study Start Date : March 2007
Actual Primary Completion Date : March 2007
Actual Study Completion Date : March 2007

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: Fed 1000 mg PA-824
Each dose will be 1000 mg PA-824 (5 x 200 mg tablets), and will be administered with 240 mL tap water approximately 30 minutes after a high-calorie, high-fat breakfast provided after a minimum 10-hour overnight fast.
Drug: PA-824 1000 mg
Two single administrations of 1000mg each administered by 5 tablets of 200mg, one administered in the fed state and one administered in the fasted state.

Experimental: Fasting 1000 mg PA-824
Each dose will be 1000 mg PA-824 (5 x 200 mg tablets), and will be administered with 240 mL tap water after a minimum 10-hour overnight fast.
Drug: PA-824 1000 mg
Two single administrations of 1000mg each administered by 5 tablets of 200mg, one administered in the fed state and one administered in the fasted state.




Primary Outcome Measures :
  1. Time of maximum drug concentration in hours [Tmax] [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare the rate and extent of absorption as measured by Tmax of a single 1000 mg oral dose of PA-824 tablets 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.

  2. Maximum observed drug concentration in ng/mL [Cmax] [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare the rate and extent of absorption as measured by Cmax of a single 1000 mg oral dose of PA-824 tablets 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.

  3. Area under the drug concentration-time curve in ng*hour/mL [AUC0-t] [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare the rate and extent of absorption as measured by AUC0-t of a single 1000 mg oral dose of PA-824 tablets 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.

  4. Area under the drug concentration-time curve from time zero to infinity in ng*hour/mL [AUC(0-inf)] [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare the rate and extent of absorption as measured by AUC0-inf of a single 1000 mg oral dose of PA-824 tablets 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.


Secondary Outcome Measures :
  1. Ratio of AUC(0-t) to AUC(0-inf) [AUC(0-t)/ AUC(0-inf)] [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare additional pharmacokinetic (PK) parameters such as AUC(0-t)/ AUC(0-inf) of a single 1000 mg oral dose of PA-824 tablets 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.

  2. Number of participants with adverse events [ Time Frame: through the study (Day 1-Day 17) ]
    To compare the safety and tolerability as measured by the number of participants with adverse events after a single 1000-mg oral dose of PA-824 tablets 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.

  3. Elimination half-life in hours [t1/2] [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare additional pharmacokinetic (PK) parameters such as t1/2 of a single 1000 mg oral dose of PA-824 tablets 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.

  4. Terminal elimination rate constant in 1/hour [Kel] [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare additional pharmacokinetic (PK) parameters such as Kel of a single 1000 mg oral dose of PA-824 tablets 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.

  5. Oral clearance in L/hour (Cl/F) [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare additional pharmacokinetic (PK) parameters such as Cl/F of a single 1000 mg oral dose of PA-824 tablets 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).

  6. Volume of distribution in L (Vd/F) [ Time Frame: mean through 168 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post dose ]
    To compare additional pharmacokinetic (PK) parameters such as Vd/F of a single 1000 mg oral dose of PA-824 tablets 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 the ratio of CL/F/Kel.



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Ages Eligible for Study:   19 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Have the ability to understand the requirements of the study, have provided written informed consent (as evidenced by signature on an informed consent document approved by an IRB), and agree to abide by the study restrictions.
  2. Be healthy non-tobacco/nicotine using (6-month minimum) adult subjects, 19 to 50 years of age, inclusive.
  3. Be medically healthy subjects with clinically insignificant Screening results (among laboratory profiles, medical histories, ECGs, or physical exam), as deemed by the Principal Investigator.
  4. Have a body mass index of 18 to 29.
  5. Have negative urine test results for alcohol and drugs of abuse such as amphetamines, cannabinoids, and cocaine metabolites at both Screening and Check-in.
  6. Agree to follow the requirements set forth in the protocol regarding pregnancy controls and donation of sperm, blood, or blood components.

Exclusion Criteria:

  1. Any clinically significant (as deemed by the Principal Investigator) history, acute illness (resolved within 4 weeks of screening), or presence of cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal (including eating disorders), endocrine, metabolic, immunologic, dermatologic, neurologic, psychological, or psychiatric disease.
  2. Any serum creatinine or BUN measure beyond the upper limit of the normal range at Screening or Check-in. Individual values may be discussed with the Sponsor Medical Monitor.
  3. Positive Screening test for HCV, HBV, or HIV.
  4. History of peptic ulcer disease, gastritis, esophagitis, or gastroesophageal reflux disease.
  5. History of any cardiac abnormality (as deemed by the Principal Investigator).
  6. History of hypokalemia or hypomagnesemia.
  7. History of prolonged QT interval.
  8. Family history of Long-QT Syndrome or sudden death without a preceding diagnosis of a condition that could be causative of sudden death (such as known coronary artery disease or CHF or terminal cancer)
  9. Resting pulse rate < 40 or > 100 bpm at Screening.
  10. At either Screening or the pre-dose read before the first dose, a QTcB (Bazett's correction) >430 msec, calculated from the average of triplicate reads collected at one sitting.
  11. At either Screening or the pre-dose read before the first dose, a QTcF (Fridericia's correction) >430 msec, calculated from the average of triplicate reads collected at one sitting.
  12. History or presence of alcoholism or drug abuse within the past 2 years (as deemed by the Principal Investigator).
  13. Use of alcohol within 72 hours prior to dosing.
  14. Significant history of drug and/or food allergies (as deemed by the Principal Investigator).
  15. For women, lactation.
  16. For women, positive test for serum HCG at Screening or Check-in.
  17. Use of any systemic or topical prescription medication within 14 days prior to dosing or during the study, except hormonal contraceptives in women.
  18. Use of any systemic or over-the-counter medication including vitamins, herbal preparations, antacids, cough and cold remedies, etc., within 7 days prior to dosing or during the study.
  19. Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes (including xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan, etc.) or known to prolong the QT interval (including amiodarone, bepridil chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine, etc.).
  20. Use of any therapeutic agents known to alter any major organ function (e.g., barbiturates, opiates, phenothiazines, cimetidine, etc.) within 30 days prior to dosing.
  21. Consumption of products containing grapefruit within 10 days prior to dosing.
  22. Any special dietary changes during the 30 days prior to dosing, as deemed by the Principal Investigator in consultation with the Sponsor Medical Monitor.
  23. Any strenuous exercise within 7 days of Check-in, as deemed by the Principal Investigator in consultation with the Sponsor Medical Monitor.
  24. Donation of whole blood or significant loss of blood within 56 days prior to dosing.
  25. Plasma donation within 7 days prior to dosing.
  26. Participation in another interventional clinical trial within 30 days prior to dosing.
  27. Hemoglobin < 12.0 g/dL.
  28. Previous use of PA-824.
  29. Any other factor which suggests to the Principal Investigator that the subject should not participate in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01828827


Locations
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United States, Nebraska
MDS Pharma Services
Lincoln, Nebraska, United States, 68502
Sponsors and Collaborators
Global Alliance for TB Drug Development
Investigators
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Principal Investigator: C James Kissling, MD MDS Pharma Services

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT01828827     History of Changes
Other Study ID Numbers: PA-824 CL-003
First Posted: April 11, 2013    Key Record Dates
Last Update Posted: January 14, 2016
Last Verified: August 2015

Keywords provided by Global Alliance for TB Drug Development:
tuberculosis
PK
PA-824
food effect,
bioavailability
pretomanid
CL-003

Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections