Single-dose Study in Two Panels of Healthy Adult Participants to Assess Immediate-Release and Dispersible Formulations of Pretomanid

This is a single-dose, open-label, randomized, four-period, four-treatment, crossover study in healthy adult subjects. Each panel of 24 subjects will be randomized according to the same 4-sequence, 4- period Williams design, in which each participant will receive four single-dose treatments. Subjects in Panel 1 will receive all treatments after consuming an FDA standard high-fat, high-calorie breakfast following an overnight fast of at least 10 hours. Subjects in Panel 2 will receive all treatments directly following an overnight fast of at least 10 hours. The two panels will be investigated concurrently.

• Pretomanid (Drug), also known as PA-824: 1. Treatment A (reference) = 200 mg given as a single 200 mg tablet (using the immediate release formulation), orally administered. 2. Treatment B (test) = 200 mg given as four 50-mg tablets (using the dispersible pediatric formulation), orally administered. 3. Treatment C (test) = single 50-mg dispersible tablet, orally administered. 4. Treatment D (test) = single 10-mg dispersible tablet, orally administered.

Primary outcomes

• Relative Bioavailability - Cmax [intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose]: Relative bioavailability will be determined separately for each panel using Cmax
• Relative Bioavailability - AUC 0-t [intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose]: Relative bioavailability will be determined separately for each panel using AUC 0-t (area under the time vs concentration curve from time 0 to time t : h*ng/mL)
• Relative Bioavailability - AUC 0-inf [intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose]: Relative bioavailability will be determined separately for each panel using AUC 0-inf (area under the time vs concentration curve from time 0 to infinite time)

Secondary outcomes

• Food Effect - Ratio of Cmax Fed Vs Fasted [intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose]: Food effect on bioavailability will be determined across panels using Cmax. Reported in Ratio(%) of the Geometric Mean (Fed)/Geometric Mean (Fasted) based on Least Squares Mean of log-transformed parameter values (ng/mL)
• Food Effect - Ratio of AUC 0-t Fed Vs Fasted [intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose]: Food effect on bioavailability was assessed across panels based on the 90% confidence intervals (CIs) for estimates of the geometric mean ratios between AUC 0-t of fed versus fasted across panels. An analysis of variance was used for each treatment with panel as the fixed effect.
• Food Effect - Ratio of AUC 0-inf Fed Vs Fasted [intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose]: Food effect on bioavailability was assessed across panels based on the 90% confidence intervals (CIs) for estimates of the geometric mean ratios between AUC 0-inf of fed versus fasted across panels. An analysis of variance was used for each treatment with panel as the fixed effect
• Adverse Events - Overall Incidence [throughout the study, approximately 33 days]: All listed adverse events (AEs) are treatment emergent adverse events (TEAE) which are defined as AEs that started or worsened at or after the first administration of IMP up to and including

Sex: All, ages: 19 Years to 50 Years, accepts healthy volunteers

Key Inclusion Criteria:

* Male or female. Females must not be pregnant or breastfeeding.
* Willing and able to comply with the contraception requirements.
* Between 19 and 50 years of age (inclusive) at the time of screening.
* Body mass index (BMI) between 18.50 and 32 kg/m2 (inclusive) and weighs a minimum of 50 kg.

Key Exclusion Criteria:

* History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results.
* Vital signs at screening (measured sitting after a minimum 3 minutes rest) as follows: blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg or a heart rate lower than 40 bpm or higher than 99 bpm. Out-of-range vital signs may be repeated once.
* History or presence of allergic or adverse response to pretomanid or related drugs.
* Use of any drugs or treatment with any known drugs that are moderate or strong inducers or inhibitors of cytochrome P450 (CYP) enzymes (e.g., barbiturates, phenothiazines, cimetidine, carbamazepine) and/or P-gp, including St. John's Wort, within 30 days before the first dose of study medication, and that, in the Investigator's judgment, may impact subject safety or the validity of the study results.
* Female with a positive pregnancy test result.
* Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) at screening or has been previously treated for hepatitis B, hepatitis C, or HIV infection.
* Hemoglobin <10.0 g/dL.
* ALT (alanine transaminase) or AST (aspartate aminotransferase) >2.0 x the upper limit of normal (ULN).
* Hyperbilirubinemia >1.5 x ULN.
* History or presence of alcoholism or drug abuse within the past 2 years as determined by the Investigator to be clinically relevant.
* Any clinically significant electrocardiogram abnormality at Screening (as deemed by decision of the Investigator and the Study Sponsor's Medical Monitor).
* QTcF interval >450 msec for males or >470 msec for females at screening, Day -1, or Day 1 (pre-dose), or history of prolonged QT syndrome.
* 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, congestive heart failure or terminal cancer).

Participant flow

Outcome results

• Relative Bioavailability - Cmax (Primary), Mean, ng/mL: Panel 1: Pretomanid After Meal 2170 +/- 484; Panel 2: Pretomanid After Fast 1180 +/- 401 (p 0.0001)
• Relative Bioavailability - AUC 0-t (Primary), Mean, h*ng/mL: Panel 1: Pretomanid After Meal 54900 +/- 10700; Panel 2: Pretomanid After Fast 32900 +/- 7580 (p 0.6686)
• Relative Bioavailability - AUC 0-inf (Primary), Mean, h*ng/mL: Panel 1: Pretomanid After Meal 57400 +/- 12300; Panel 2: Pretomanid After Fast 34700 +/- 8330 (p 0.4683)
• Food Effect - Ratio of Cmax Fed Vs Fasted (Secondary), Number, Ratio (%): Treatment A Fed and Fasted 187.65 (165.90 to 212.25); Treatment B Fed and Fasted 173.24 (153.26 to 195.82); Treatment C Fed and Fasted 93.25 (83.16 to 104.56); Treatment D Fed and Fasted 69.38 (61.96 to 77.68)
• Food Effect - Ratio of AUC 0-t Fed Vs Fasted (Secondary), Number, Ratio (%): Treatment A Fed and Fasted 167.96 (151.40 to 186.33); Treatment B Fed and Fasted 188.36 (165.60 to 214.26); Treatment C Fed and Fasted 114.09 (99.70 to 130.55); Treatment D Fed and Fasted 81.74 (71.53 to 93.42)
• Food Effect - Ratio of AUC 0-inf Fed Vs Fasted (Secondary), Number, Ratio (%): Treatment A Fed and Fasted 166.38 (149.07 to 185.69); Treatment B Fed and Fasted 187.54 (163.44 to 215.20); Treatment C Fed and Fasted 113.58 (98.52 to 130.95); Treatment D Fed and Fasted 81.57 (71.07 to 93.61)
• Adverse Events - Overall Incidence (Secondary), Count of participants, Participants: Panel 1: Treatment A 5; Panel 1: Treatment B 9; Panel 1: Treatment C 2; Panel 1: Treatment D 6; Panel 2:Treatment A 3; Panel 2: Treatment B 3; Panel 2: Treatment C 1; Panel 2: Treatment D 4

Adverse events

Time frame: Day 1 to Day 33

Other adverse events by term

• Results publication: Zou Y, Nedelman J, Lombardi A, Pappas F, Karlsson MO, Svensson EM. Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling. Clin Pharmacokinet. 2022 Nov;61(11):1585-1593. doi: 10.1007/s40262-022-01163-w. Epub 2022 Sep 30. PMID 36180816

• Study Protocol (PDF, 2019-12-06)
• Statistical Analysis Plan (PDF, 2020-03-09)

• Antonio Lombardi, MD, Study director, TB Alliance