Pretomanid in Adults With Hepatic Impairment

A Phase I, Single Dose, Open-Label Study Comparing the Pharmacokinetics and Safety of Pretomanid in Subjects With Mild, Moderate, and Severe Hepatic Impairment to Matched, Non-Hepatically Impaired Subjects

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02422524

Enrollment

Registered

2015-04-21

Start date

2018-03-29

Completion date

2023-11-17

Last updated

2025-06-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Tuberculosis

Keywords

Hepatic, impairment, PA-824, Pharmacokinetics, Safety, Tuberculosis

Brief summary

This is a Phase 1, single dose (200 mg), open-label study comparing the pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 2 sites, study duration is approximately 24 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.

Detailed description

This is a Phase 1, single dose (200 mg), open-label study comparing the pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. This study will enroll approximately 6 subjects with mild hepatic impairment (Child-Pugh A), approximately 6 subjects with moderate hepatic impairment (Child-Pugh B), approximately 6 subjects with severe hepatic impairment (Child-Pugh C), and approximately 18 matched non-hepatically impaired subjects. Non-hepatically impaired subjects in the control group will be matched to subjects with hepatic impairment based on age (+/- 10 years) and body weight (+/- 20 percent) as measured at screening (Visit 00A). There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 2 sites, study duration is approximately 24 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.

Interventions

DRUGPA-824

Pretomanid (PA-824) is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg Pretomanid on day 1.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Yes

Inclusion criteria

Inclusion Criteria for Patients with Hepatic Impairment (Groups 1-3): 1. Subject is able to give voluntary written informed consent before any study related procedure is performed. 2. 18-70 years of age, inclusive. 3. Acceptable laboratory values\* obtained at screening (within 21 days prior to admission to the confinement/hospital unit) and either at or within 72 hours of admission to the confinement/hospital unit. \*Chemistry, complete blood count, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), total bilirubin, alkaline phosphatase, albumin, and urinalysis deemed not clinically significant by the investigator. 4. Hepatic impairment classified as Child-Pugh class A (mild), B (moderate), or C (severe) criteria at screening for Groups 1, 2, or 3, respectively, and documented evidence of hepatic cirrhosis\*. \*by biopsy, nuclear scan, CT, MRI, ultrasound, or other clinically acceptable methods 5. If female, not of childbearing potential\* or agrees to avoid becoming pregnant by using acceptable contraception\*\* during the duration of the study. \*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy or status after hysterectomy. * Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual intercourse with men. 6. If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after dosing by using an acceptable method of birth control\*. \*In addition to the use of a barrier method (condom) even if vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #5, and abstinence from sexual intercourse with women. 7. If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy test at admission to the confinement/hospital unit. 8. Willingness to comply with all protocol requirements. Inclusion Criteria for Non-Hepatically Impaired Controls (Group 4): 1. Subject is able to give voluntary written informed consent before any study related procedure is performed. 2. 18-70 years of age, inclusive. 3. Subject is a healthy volunteer as determined by no clinically significant findings from medical history, physical examination, vital signs, and 12-lead ECG as determined by the Site Investigator. 4. Acceptable laboratory values\* obtained at screening (within 21 days prior to admission to the confinement/hospital unit) and either at or within 72 hours of admission to the confinement/hospital unit. \*Chemistry, complete blood count, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), total bilirubin, alkaline phosphatase, albumin, and urinalysis within the reference range for the test laboratory, unless deemed not clinically significant by the investigator. 5. If female, not of childbearing potential\* or agrees to avoid becoming pregnant by using acceptable contraception\*\* during the duration of the study. \*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy or status after hysterectomy. \*\*Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual intercourse with men. 6. If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after dosing by using an acceptable method of birth control\*. \*In addition to the use of a barrier method (condom) even if vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #5, and abstinence from sexual intercourse with women. 7. If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy test at admission to the confinement/hospital unit. 8. Willingness to comply with all protocol requirements.

Design outcomes

Primary

Measure	Time frame	Description
Vd/F: Apparent Volume of Distribution at Specified Pre-dose and Post-dose Time Points	Day 1 to Day 5	Apparent Volume of Distribution at specified pre-dose and post-dose timepoints is the volume that the total amount of administered drug would occupy to provide the same concentration as it currently is in blood plasma divided by the bioavailability. It is calculated by Dose/\[Lambda\_z x AUC(0-infinity)\]
AUC(0-infinity): Area Under the Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points	Day 1 to Day 5	AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant.
AUC(0-last): Area Under the Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points	Day 1 to Day 5	AUC(0-last) Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points was calculated by noncompartmental analysis using the linear up log down method.
CL/F: Apparent Oral Clearance Calculated From Dose/AUC(0-infinifty) at Specified Pre-dose and Post-dose Time Points	Day 1 to Day 5	Apparent oral clearance was calculated by noncompartmental analysis using the formula Dose/AUC(0-infinity).
Cmax: Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points	Day 1 to Day 5	Maximum Pretomanid concentration is the maximum observed drug concentration in blood plasma at specified pre-dose and post-dose timepoints.
t(1/2): Apparent Terminal Elimination Half-life at Specified Pre-dose and Post-dose Time Points	Day 1 to Day 5	Apparent terminal half-life at specified pre-dose and post-dose timepoints was estimated by ln(2)/Lambda\_z, where Lambda\_z is the elimination rate constant.
Tmax: Time of Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points	Day 1 to Day 5	Time of maximum Pretomanid concentration (Tmax) at specified pre-dose and post-dose timepoints.

Secondary

Measure	Time frame	Description
Incidence and Severity of Serious Adverse Events	Day 1 to Day 12	A serious adverse event (SAE) is any adverse event occurring at any dose and regardless of causality that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, is a congenital anomaly or birth defect in an offspring of a subject taking study drug, or is an important medical event.
Number of Participants With Abnormal ECG Data	Day 12	ECG data was collected, including PR interval, QRS duration, QT Interval, QTc interval, RR interval, and Ventricular rate. Abnormal ECG data was evaluated for clinical significance.
Number of Participants With Abnormal Physical Exam Findings	Day 3, 4, 5 and 12	Summary of physical examination findings were obtained from a comprehensive physical examination including the following body system assessments: skin; head, eyes, ears, nose, and throat; thyroid; neurological; chest and lungs; cardiovascular; abdomen (liver and spleen); lymph nodes; musculoskeletal, and extremities.
Number of Participants With Abnormal Safety Laboratory Parameters	Day 2, 5, and 12	Summary of abnormal laboratory parameters were collected following dose of study product through day 12. Abnormal findings were evaluated based on relationship to study product and clinical significance.
Number of Participants With Abnormal Vital Signs	Days 1, 2, 3, 4, 5, and 12	Vital signs were collected at each study visit following study product administration. Abnormal vital signs were graded as mild, moderate or severe.
Incidence and Severity of Related Adverse Events	Day 1 to Day 12	Events were determined to be related if there was a reasonable possibility that the study product caused the adverse event (AE); that is, there was evidence to suggest a causal relationship between the study product and the AE. Each event was graded as mild, moderate or severe. Participants are counted according to their maximum severity of the event reported.

Countries

United States

Participant flow

Recruitment details

Participants were hepatically impaired or non-hepatically impaired males and females, 18 to 70 years of age, inclusive, and met all eligibility criteria. Enrollment occurred between 29MAR2018 and 22AUG2023.

Participants by arm

Arm	Count
Mild Hepatic Impairment Participants with mild hepatic impairment received a single oral dose of 200mg Pretomanid tablets on day 1	6
Moderate Hepatic Impairment Participants with moderate hepatic impairment received a single oral dose of 200mg Pretomanid tablets on day 1	2
Severe Hepatic Impairment Participants with severe hepatic impairment received a single oral dose of 200mg Pretomanid tablets on day 1	0
Non-hepatically Impaired Controls Participants with no hepatic impairment received a single oral dose of 200mg Pretomanid tablets on day 1	6
Total	14

Baseline characteristics

Characteristic	Non-hepatically Impaired Controls	Mild Hepatic Impairment	Total	Moderate Hepatic Impairment	Severe Hepatic Impairment
Age, Continuous	59 years STANDARD_DEVIATION 7.1	62.8 years STANDARD_DEVIATION 4.1	60.9 years STANDARD_DEVIATION 5.5	60.5 years STANDARD_DEVIATION 3.5	—
BMI	27.9 kg/m^2 STANDARD_DEVIATION 4.4	31.3 kg/m^2 STANDARD_DEVIATION 8	31.4 kg/m^2 STANDARD_DEVIATION 6.3	36.5 kg/m^2 STANDARD_DEVIATION 5	—
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants	6 Participants	14 Participants	2 Participants	0 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Height	172.5 cm STANDARD_DEVIATION 8.6	172.6 cm STANDARD_DEVIATION 8.2	171.7 cm STANDARD_DEVIATION 8.34	166.4 cm STANDARD_DEVIATION 12.6	—
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	4 Participants	3 Participants	7 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	2 Participants	3 Participants	7 Participants	2 Participants	0 Participants
Region of Enrollment United States	6 participants	6 participants	14 participants	2 participants	—
Sex: Female, Male Female	1 Participants	2 Participants	4 Participants	1 Participants	0 Participants
Sex: Female, Male Male	5 Participants	4 Participants	10 Participants	1 Participants	0 Participants
Weight	88.9 kg STANDARD_DEVIATION 19.5	92.9 kg STANDARD_DEVIATION 21.8	92.5 kg STANDARD_DEVIATION 20.4	102.4 kg STANDARD_DEVIATION 29.2	—

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 2	0 / 0	0 / 6
other Total, other adverse events	3 / 6	1 / 2	0 / 0	4 / 6
serious Total, serious adverse events	0 / 6	0 / 2	0 / 0	0 / 6

Outcome results

Primary

AUC(0-infinity): Area Under the Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points

AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant.

Time frame: Day 1 to Day 5