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Single-Dose Study to Evaluate the PKs of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03896750
Recruitment Status : Recruiting
First Posted : April 1, 2019
Last Update Posted : December 23, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
This is a Phase I, open-label, single dose, sequential group study to compare the safety and pharmacokinetics of pretomanid in the following two groups of subjects: 1) those with mild, moderate, and severe renal impairment including those with End Stage Renal Disease (ESRD) not needing dialysis; and 2) matched subjects with normal renal function. The study will be conducted in two parts. Part A will enroll subjects from Groups 1A and 2 (i.e. 6 healthy matched controls and 6 subjects with ESRD, not on dialysis). A decision to enroll subjects into Part B (i.e. to investigate mild, moderate and severe renal impairment) will be conducted after the pharmacokinetics (PK) of the parent compound and safety of subjects enrolled in Part A have been reviewed. Part B will be conducted if the results of Part A demonstrate that patients with ESRD, not on dialysis have different exposures to pretomanid that may impact safety or efficacy relative to the exposures of healthy subjects. If the decision is taken to conduct Part B, 6 subjects each with mild, moderate and severe renal impairment (Groups 3, 4, 5) will be enrolled together with additional healthy matched subjects (Groups 1B-1D). Part B, treatment Groups 3, 4, and 5 will be initiated concurrently when each subject in Groups 1A and 2 has completed Part A of the study. The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK of pretomanid after a single oral dose of 200 mg in subjects with renal impairment compared to matched healthy controls.

Condition or disease Intervention/treatment Phase
Renal Impairment Tuberculosis Drug: PA-824 Phase 1

Detailed Description:
This is a Phase I, open-label, single dose, sequential group study to compare the safety and pharmacokinetics of pretomanid in the following two groups of subjects: 1) those with mild, moderate, and severe renal impairment including those with End Stage Renal Disease (ESRD) not needing dialysis; and 2) matched subjects with normal renal function. The study will be conducted in two parts. Part A will enroll subjects from Groups 1A and 2 (i.e. 6 healthy matched controls and 6 subjects with ESRD, not on dialysis). A decision to enroll subjects into Part B (i.e. to investigate mild, moderate and severe renal impairment) will be conducted after the pharmacokinetics (PK) of the parent compound and safety of subjects enrolled in Part A have been reviewed. Part B will be conducted if the results of Part A demonstrate that patients with ESRD, not on dialysis have different exposures to pretomanid that may impact safety or efficacy relative to the exposures of healthy subjects. If the decision is taken to conduct Part B, 6 subjects each with mild, moderate and severe renal impairment (Groups 3, 4, 5) will be enrolled together with additional healthy matched subjects (Groups 1B-1D). Part B, treatment Groups 3, 4, and 5 will be initiated concurrently when each subject in Groups 1A and 2 has completed Part A of the study. The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK of pretomanid after a single oral dose of 200 mg in subjects with renal impairment compared to matched healthy controls. The secondary objectives are 1) to assess the safety profile of a single oral dose of 200 mg pretomanid in renally impaired subjects to matched healthy controls; and 2) to measure representative plasma pretomanid metabolites (M19 and M50) for analysis.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics and Safety of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function
Actual Study Start Date : August 1, 2019
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : October 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Tests

Arm Intervention/treatment
Active Comparator: Part A Group 1A
6 healthy participants with normal estimated Glomerular Filtration Rate (eGFR > / = 90 mL/min/1.73 m^2) matched to Group 2 by race, gender, age (+/- 10 years, but between 18 to 70 years of age) and BMI at dosing (+/- 20% of BMI, but between 18 and 35 kg/m^2) will receive a single oral dose of 200 mg pretomanid
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Experimental: Part A Group 2
6 participants with End Stage Renal Disease (ESRD) not on dialysis: Stage 5, Modification of Diet in Renal Disease (MDRD) with estimated Glomerular Filtration Rate (eGFR < 15 mL/min/1.73 m^2) matched to Group 1A will receive a single oral dose of 200 mg pretomanid
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Active Comparator: Part B Group 1B
6 healthy participants with normal eGFR of > / = 90 mL/min/1.73 m^2 matched to Group 3 by race, gender, age (+/- 10 years, but between 18 to 70 years of age) and BMI at dosing (+/- 20% of BMI, but between 18 and 35 kg/m^2) will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Active Comparator: Part B Group 1C
6 healthy participants with normal eGFR > / = 90 mL/min/1.73 m^2 matched to Group 4 by race, gender, age (+/- 10 years, but between 18 to 70 years of age) and BMI at dosing (+/- 20% of BMI, but between 18 and 35 kg/m^2) will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Active Comparator: Part B Group 1D
6 healthy participants with normal eGFR > / = 90 mL/min/1.73 m^2 matched to Group 5 by race, gender, age (+/- 10 years, but between 18 to 70 years of age) and BMI at dosing (+/- 20% of BMI, but between 18 and 35 kg/m^2) will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Experimental: Part B Group 3
6 participants with mild renal impairment: Stage 2, MDRD (eGFR 60-89 mL/min/1.73 m^2) matched to Group 1B will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Experimental: Part B Group 4
6 participants with moderate renal impairment: Stage 3, MDRD (eGFR = 30-59 mL/min/1.73 m^2) matched to Group 1C will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Experimental: Part B Group 5
6 participants with severe renal impairment: Stage 4, MDRD (eGFR = 15-29 mL/min/1.73 m^2) matched to Group 1D will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed
Drug: PA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.




Primary Outcome Measures :
  1. Apparent clearance of drug from plasma after drug administration (CL/F) [ Time Frame: Up to 96 hours ]
  2. Apparent volume of distribution (Vd/F) [ Time Frame: Up to 96 hours ]
  3. Area under the plasma concentration-time curve from time zero to infinity (AUC-infinity) [ Time Frame: Up to 96 hours ]
  4. Area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) [ Time Frame: Up to 96 hours ]
  5. Fraction of Pretomanid bound to protein in plasma [ Time Frame: Up to 96 hours ]
  6. Maximum plasma concentration of pretomanid (Cmax) [ Time Frame: Up to 96 hours ]
  7. Terminal-phase elimination half-life (t1/2) [ Time Frame: Up to 96 hours ]
  8. Time to peak (maximum) (Tmax) [ Time Frame: Up to 96 hours ]

Secondary Outcome Measures :
  1. Mean change from baseline in alanine aminotransferase (ALT) [ Time Frame: Through Day 12 ]
  2. Mean change from baseline in aspartate aminotransferase (AST) [ Time Frame: Through Day 12 ]
  3. Mean change from baseline in blood urea nitrogen (BUN) [ Time Frame: Through Day 12 ]
  4. Mean change from baseline in creatinine [ Time Frame: Through Day 12 ]
  5. Mean change from baseline in estimated glomerular filtration rate (eGFR) [ Time Frame: Through Day 12 ]
  6. Mean change from baseline in hemoglobin [ Time Frame: Through Day 12 ]
  7. Mean change from baseline in magnesium [ Time Frame: Through Day 12 ]
  8. Mean change from baseline in potassium [ Time Frame: Through Day 12 ]
  9. Mean change from baseline in total bilirubin [ Time Frame: Through Day 12 ]
  10. Mean change in blood pressure from baseline [ Time Frame: Through Day 12 ]
  11. Mean change in oral temperature from baseline [ Time Frame: Through Day 12 ]
  12. Mean change in pulse from baseline [ Time Frame: Through Day 12 ]
  13. Mean change in the ECG QTc interval from baseline [ Time Frame: Through Day 5 ]
  14. Number of subjects reporting adverse events (AEs) [ Time Frame: Day 1 to Day 12 ]
  15. Plasma levels of representative metabolites [ Time Frame: Up to 96 hours ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Subject Inclusion Criteria for Patients with Renal Impairment (Groups 2-5)

  1. Have the ability to understand the requirements of the study and have provided written informed consent* before any study related procedure is performed.

    *As evidence by signature on an informed consent document approved by the IRB

  2. Agree to abide by the study restrictions.
  3. Are between the ages of 18 and 70, inclusive, at the time of enrollment.
  4. Must have mild, moderate, severe or end stage renal disease but are not on dialysis.
  5. Are free from tobacco/nicotine usage (30-day minimum from screening visit).
  6. Have QTc interval on electrocardiogram (ECG) < 500 msec.
  7. Have a body mass index of 18 to 35 kg/m^2.
  8. Women of childbearing potential** must use an acceptable contraception method*** for the duration of the study.

    **Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, implanted contraceptive device placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or < 1 year has passed since the last menses if menopausal.

    ***Includes, non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving study product, barrier methods such as condoms or diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables or oral contraceptives ("the pill").

  9. If subject is male and capable of reproduction, agrees to avoid fathering a child for the duration of the study by using an acceptable method of birth control****.

    ****In addition to the use of a barrier method (condom) unless 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 #8, and/or abstinence from sexual intercourse with women.

  10. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product

Subject Inclusion Criteria for Healthy Subjects (Groups 1A-1D)

  1. Have the ability to understand the requirements of the study and have provided written informed consent* before any study related procedure is performed.

    *As evidence by signature on an informed consent document approved by the IRB.

  2. Agree to abide by the study restrictions.
  3. Are healthy male or non-pregnant female, between the ages of 18 and 70, inclusive, with normal GFR > / = 90 at screening.
  4. Are free from tobacco/nicotine usage (30-day minimum from screening visit).
  5. Have a normal QTc interval < 500 msecs on electrocardiogram (ECG).
  6. Have a body mass index of 18 to 35 kg/m^2.
  7. Women of childbearing potential** must use an acceptable contraception method*** for the duration of the study.

    • Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, implanted contraceptive device placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or <1 year has passed since the last menses if menopausal.

      • Includes, non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving study product, barrier methods such as condoms or diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables or oral contraceptives ("the pill").
  8. If subject is male and capable of reproduction, agrees to avoid fathering a child for the duration of the study by using an acceptable method of birth control****.

    ****In addition to the use of a barrier method (condom) unless 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 #7, and/or abstinence from sexual intercourse with women.

  9. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product

Exclusion Criteria:

Subject Exclusion Criteria for Patients with Renal Impairment (Groups 2-5)

  1. History of known active TB.
  2. History of peptic ulcer disease
  3. Have known hypersensitivity to pretomanid or any of the excipients
  4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI)).
  5. Any clinically significant ECG abnormality at screening* *Note: the following can be considered not clinically significant:

    • Heart rate < / = 50 beats per minute (bpm) (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 seconds)
    • Right or left axis deviation
    • Incomplete right bundle branch block
    • Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic subjects
  6. History of or screening results show a QTc interval > / = 500 msecs.
  7. 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 congestive heart failure (CHF) or terminal cancer.

  8. Inability to swallow tablets.
  9. History of fever or documented fever (oral temperature > 100.4 degrees Fahrenheit) in the 48 hours prior to admission to the hospital.
  10. Resting pulse rate <50 or > 100 bpm at Screening.
  11. At Screening blood pressure > / = 20 mm Hg systolic or 10 mm Hg diastolic above baseline**** (sitting).

    ****Baseline is most recent blood pressure in the last 3 months if not similar to control group.

  12. Current hypokalemia or hypomagnesemia.
  13. Positive result of urine drug screen or blood alcohol screen prior to hospital admission.
  14. Significant history of drug and/or food allergies (as deemed by the PI).
  15. For women, subject is pregnant (positive test for urine HCG at Screening or Check-in), breastfeeding or planning to conceive for the duration of the study.
  16. Women who are breastfeeding or lactating.
  17. Any contraindication to the use of nitromidazoles, or prior treatment with pretomanid or delamanid.
  18. Treatment with strong CYP450 enzyme inducers or inhibitors***** within 7 days prior to admission or during the study, unless****** the substance would not likely impact the validity of the study results.

    *****except hormonal contraceptives

    ******in the opinion of the site investigator

  19. 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 and during the entire study.
  20. Use of St. John's Wort within 7 days prior to admission and during the entire study.
  21. Consumption of products containing grapefruit within 5 days prior to dosing until discharged from the hospital.
  22. Donation of whole blood or blood products > 500 mL within 30 days and plans to donate during the study or up to 14 days after dosing.
  23. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit.
  24. Hemoglobin < 9.0 g/dL in both men and women at the screening visit.
  25. Positive Screening test for HCV, HBV, or HIV.
  26. Renal transplant.
  27. Scheduled for hemodialysis or peritoneal dialysis
  28. Presence of any condition or finding******* which would jeopardize subject safety, impact study result validity, or diminish the subject's ability to undergo all study procedures and assessments.

    *******In the opinion of the investigator

  29. Semen donation for the duration of the study.
  30. AST and ALT > 2.0 x ULN.
  31. Hyperbilirubinemia > 1.5 x ULN.

Subject Exclusion Criteria for Healthy Subjects (Groups 1A-1D)

  1. History of known active TB.
  2. History of peptic ulcer disease
  3. Have known hypersensitivity to pretomanid or any of the excipients
  4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI).
  5. Any clinically significant ECG abnormality at screening*.

    *Note: the following can be considered not clinically significant:

    • Heart rate > / = 50 beats per minute (bpm) (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 seconds)
    • Right or left axis deviation
    • Incomplete right bundle branch block
    • Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic subjects
  6. 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 congestive heart failure (CHF) or terminal cancer.

  7. Inability to swallow tablets.
  8. History of fever or documented fever (oral temperature > / = 100.4 degrees Fahrenheit) in the 48 hours prior to admission to the hospital.
  9. Resting pulse rate < 50 or > 100 bpm at Screening.
  10. At Screening blood pressure > 140/90 mm Hg or < 90/65 mm Hg (sitting).
  11. History of or screening results show a QTc interval > / = 500 msecs.
  12. History of hypokalemia or hypomagnesemia.
  13. Positive result of urine drug screen or blood alcohol screen prior to hospital admission.
  14. Significant history of drug and/or food allergies (as deemed by the PI).
  15. For women, subject is pregnant (positive test for urine HCG at Screening or hospital admission), breastfeeding or planning to conceive for the duration of the study.
  16. Women who are breastfeeding or lactating.
  17. Any contraindication to the use of nitromidazoles, or prior treatment with pretomanid or delamanid.
  18. Treatment with strong CYP450 enzyme inducers or inhibitors*** within 7 days prior to admission or during the study, unless**** the substance would not likely impact the validity of the study results.

    ***except hormonal contraceptives

    ****in the opinion of the site investigator

  19. 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 and during the entire study.
  20. Use of St. John's Wort within 7 days prior to admission and during the entire study.
  21. Consumption of products containing grapefruit within 5 days prior to dosing until discharged from the hospital.
  22. Donation of whole blood or blood products > 500 mL within 30 days and/or plans to donate during the study or up to 14 days after dosing.
  23. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit.
  24. Hemoglobin < 10.0 g/dL in both men and women at the screening visit.
  25. Positive Screening test for HCV, HBV, or HIV.
  26. Renal transplant.
  27. Presence of any condition or finding***** which would jeopardize subject safety, impact study result validity, or diminish the subject's ability to undergo all study procedures and assessments.

    *****In the opinion of the investigator

  28. Semen donation for the duration of the study.
  29. AST and ALT > 2.0 x ULN.
  30. Hyperbilirubinemia > 1.5 x ULN.

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): NCT03896750


Contacts
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Contact: Getahun Abate 13149775500 getahun.abate@health.slu.edu

Locations
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United States, Missouri
Saint Louis University - Center for Vaccine Development Recruiting
Saint Louis, Missouri, United States, 63104-1015
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03896750    
Other Study ID Numbers: 15-0037
HHSN272201300021I
First Posted: April 1, 2019    Key Record Dates
Last Update Posted: December 23, 2019
Last Verified: June 28, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Open-Label
Pretomanid
Renal Pharmacokinetic
Safety
Single-Dose
Additional relevant MeSH terms:
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Tuberculosis
Renal Insufficiency
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Kidney Diseases
Urologic Diseases