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

NCT01828827 | Completed Phase 1

• 1 other identifier: PA-824 CL-003
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis

Keywords

tuberculosis; PK; PA-824; food effect,; bioavailability; pretomanid; CL-003

Outcome Measures

Primary Outcomes (4)

• Time of maximum drug concentration in hours [Tmax]

  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.

  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

• Maximum observed drug concentration in ng/mL [Cmax]

  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.

  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

• Area under the drug concentration-time curve in ng*hour/mL [AUC0-t]

  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.

  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

• Area under the drug concentration-time curve from time zero to infinity in ng*hour/mL [AUC(0-inf)]

  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.

  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

Secondary Outcomes (6)

• Ratio of AUC(0-t) to AUC(0-inf) [AUC(0-t)/ AUC(0-inf)]

  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

• Number of participants with adverse events

  through the study (Day 1-Day 17)

• Elimination half-life in hours [t1/2]

  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

• Terminal elimination rate constant in 1/hour [Kel]

  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

• Oral clearance in L/hour (Cl/F)

  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

Study Arms (2)

Fed 1000 mg PA-824

EXPERIMENTAL

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

Fasting 1000 mg PA-824

EXPERIMENTAL

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

Interventions

PA-824 1000 mg DRUG

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.

Fasting 1000 mg PA-824; Fed 1000 mg PA-824

Eligibility Criteria

• Age: 19 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• Be healthy non-tobacco/nicotine using (6-month minimum) adult subjects, 19 to 50 years of age, inclusive.
• Be medically healthy subjects with clinically insignificant Screening results (among laboratory profiles, medical histories, ECGs, or physical exam), as deemed by the Principal Investigator.
• Have a body mass index of 18 to 29.
• Have negative urine test results for alcohol and drugs of abuse such as amphetamines, cannabinoids, and cocaine metabolites at both Screening and Check-in.
• Agree to follow the requirements set forth in the protocol regarding pregnancy controls and donation of sperm, blood, or blood components.

You may not qualify if:

• 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.
• 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.
• Positive Screening test for HCV, HBV, or HIV.
• History of peptic ulcer disease, gastritis, esophagitis, or gastroesophageal reflux disease.
• History of any cardiac abnormality (as deemed by the Principal Investigator).
• History of hypokalemia or hypomagnesemia.
• History of prolonged QT interval.
• 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)
• Resting pulse rate \< 40 or \> 100 bpm at Screening.
• 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.
• 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.
• History or presence of alcoholism or drug abuse within the past 2 years (as deemed by the Principal Investigator).
• Use of alcohol within 72 hours prior to dosing.
• Significant history of drug and/or food allergies (as deemed by the Principal Investigator).
• For women, lactation.

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (1)

MDS Pharma Services

Lincoln, Nebraska, 68502, United States

Location

Related Publications (1)

• Winter H, Ginsberg A, Egizi E, Erondu N, Whitney K, Pauli E, Everitt D. Effect of a high-calorie, high-fat meal on the bioavailability and pharmacokinetics of PA-824 in healthy adult subjects. Antimicrob Agents Chemother. 2013 Nov;57(11):5516-20. doi: 10.1128/AAC.00798-13. Epub 2013 Aug 26.

  PMID: 23979737 DERIVED

Related Links

• Global Alliance for TB Drug Development website

MeSH Terms

Conditions

Tuberculosis

Interventions

pretomanid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• C James Kissling, MD

  MDS Pharma Services

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2013
• First Posted: April 11, 2013
• Study Start: March 1, 2007
• Primary Completion: March 1, 2007
• Study Completion: March 1, 2007
• Last Updated: January 14, 2016

Record last verified: 2015-08

Locations

US (1)