Food Effect Study on the Bioavailability and PK of PA-824 Tablets in Healthy Adult Subjects (CL-009)

NCT01830439 | Completed Phase 1

• 1 other identifier: PA-824-CL-009
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Tuberculosis

Keywords

tuberculosis; PK; PA-824; food effect; pretomanid; CL-009

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  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

Secondary Outcomes (6)

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

  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

  through the study Day 13, and through Day 103 for SAE and ophthalmologic events

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

  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]

  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]

  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

Study Arms (4)

Fed PA-824 200mg

EXPERIMENTAL

200 mg PA-824 (4 x 50 mg tablets) in Phase A was administered 30 minutes after the start of a high-calorie, high-fat breakfast provided after a minimum 10-hour overnight fast and was administered with 240 mL tap water.

Drug: PA-824 200mg

Fasted PA-824 200 mg

EXPERIMENTAL

200 mg PA-824 (4 x 50 mg tablets) in Phase A was administered 30 minutes after a minimum 10-hour overnight fast and was administered with 240 mL tap water.

Drug: PA-824 200mg

Fed PA-824 50mg

EXPERIMENTAL

50 mg PA-824 (1 x 50 mg tablets) in Phase B was administered 30 minutes after the start of a high-calorie, high-fat breakfast provided after a minimum 10-hour overnight fast and was administered with 240 mL tap water.

Drug: PA-824 50mg

Fasted PA-824 50mg

EXPERIMENTAL

50 mg PA-824 (1 x 50 mg tablets) in Phase B was administered after a minimum 10-hour overnight fast and was administered with 240 mL tap water.

Drug: PA-824 50mg

Interventions

PA-824 200mg DRUG

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.

Fasted PA-824 200 mg; Fed PA-824 200mg

PA-824 50mg DRUG

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.

Fasted PA-824 50mg; Fed PA-824 50mg

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.
• History of peptic ulcer disease, gastritis, esophagitis, or gastroesophageal reflux disease.
• History of any cardiac abnormality (as deemed by the Principal Investigator).
• Any clinically significant ECG abnormality at Screening (as deemed by the Principal Investigator and the Sponsor's Medical Monitor). Note: the following can be considered not clinically significant without consulting Sponsor's Medical Monitor:
• Sinus bradycardia with heart rate ≥50 beats per minute (sinus bradycardia with heart rate between 45 and 49, inclusive, is acceptable only in younger athletic subjects)
• Mild first degree A-V block (P-R interval \<0.23 sec)
• Right or left axis deviation
• Incomplete right bundle branch block
• Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic subjects
• 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 Screening blood pressure greater than 140/90 mm Hg or below 95/65 mm Hg (supine, after a minimum 5-minute supine rest)
• At either Screening or the pre-dose read before the first dose, a QTcB (Bazett's correction) \>450ms for men and women, 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) \>450ms for men and women, calculated from the average of triplicate reads collected at one sitting.

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (1)

MDS Pharma Services (Celerion)

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

• Scott Rasmussen, MD

  MDS Pharma Services (Celerion)

  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 12, 2013
• Study Start: September 1, 2009
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2010
• Last Updated: September 6, 2019

Record last verified: 2019-09

Locations

US (1)