A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics and Safety of Pretomanid in Participants With Renal Impairment Compared to Participants With Normal Renal Function
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 6
- 主要终点
- Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls
研究概览
简要总结
This is a Phase 1, open-label, single-dose, sequential group study to compare the safety and pharmacokinetics (PK) of pretomanid in the following groups of participants: 1) participants with severe renal impairment including those with end stage renal disease (ESRD) not on dialysis, and participants with mild or moderate renal impairment, designated as Groups 2, 3, and 4, respectively; and 2) participants with normal renal function matched to the above renal impairment groups, designated as Groups 1A, 1B, and 1C, respectively.
The study will be conducted following a reduced PK study design in Part A. Part A will enroll participants from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 6 participants with severe renal impairment and ESRD, not on dialysis). A decision to proceed to Part B will be made after the PK of pretomanid, and safety in participants enrolled in Part A have been reviewed. If Part A demonstrates at least a 50% increase in pretomanid area under the plasma concentration-time curve (AUC) in Group 2 (severe renal impairments and ESRD, not on dialysis) relative to the exposures in Group 1A (matched participants with normal renal function), then the reduced PK study will extend to the full PK study to enroll participants into Part B (i.e., to investigate mild and moderate renal impairment). All Part B groups (1B, 1C, 3, and 4) will be enrolled concurrently.
If the reduced PK study shows at least a 50% increase in AUC in patients with severe renal impairment and patients with ESRD not yet on dialysis relative to the matched healthy controls, a "full PK" renal impairment study in patients with all intermediate levels of renal function impairment should be conducted. Otherwise, no further study is recommended.
The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg in participants with renal impairment compared to matched healthy controls.
详细描述
This is a Phase 1, open-label, single-dose, sequential group study to compare the safety and pharmacokinetics (PK) of pretomanid in the following groups of participants: 1) participants with severe renal impairment including those with end stage renal disease (ESRD) not on dialysis, and participants with mild or moderate renal impairment, designated as Groups 2, 3, and 4, respectively; and 2) participants with normal renal function matched to the above renal impairment groups, designated as Groups 1A, 1B, and 1C, respectively.
The study will be conducted following a reduced PK study design in Part A. Part A will enroll participants from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 6 participants with severe renal impairment and ESRD, not on dialysis). A decision to proceed to Part B will be made after the PK of pretomanid, and safety in participants enrolled in Part A have been reviewed. If Part A demonstrates at least a 50% increase in pretomanid area under the plasma concentration-time curve (AUC) in Group 2 (severe renal impairments and ESRD, not on dialysis) relative to the exposures in Group 1A (matched participants with normal renal function), then the reduced PK study will extend to the full PK study to enroll participants into Part B (i.e., to investigate mild and moderate renal impairment). All Part B groups (1B, 1C, 3, and 4) will be enrolled concurrently.
If the reduced PK study shows at least a 50% increase in AUC in patients with severe renal impairment and patients with ESRD not yet on dialysis relative to the matched healthy controls, a "full PK" renal impairment study in patients with all intermediate levels of renal function impairment should be conducted. Otherwise, no further study is recommended.
The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg in participants 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 participants to matched healthy controls; and 2) to evaluate the PK profiles or representative pretomanid metabolites (M19 and M50) in plasma and urine.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participant Inclusion Criteria for Patients with Renal Impairment (Groups 2-4)
- •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 Institutional Review Board
- •Agree to abide by the study restrictions.
- •Are between the ages of 18 and 85 years, inclusive, at the time of enrollment.
- •Must have mild, moderate, or severe renal impairment or end stage renal disease (ESRD), but are not on dialysis.
- •Have no history of chronic tobacco/nicotine usage (i.e., >10 cigarettes per day for 3 months minimum prior to admission).
- •Have corrected QT interval by Fridericia (QTcF) <460 msec on Electrocardiogram (ECG).
- •Have a Body Mass Index (BMI) of 18 to 40 kg/m^2 at enrollment.
- •Women of childbearing potential** must use an acceptable contraception method*** for the duration of the study.
- •**Not sterilized via tubal ligation, bilateral oophorectomy, bilateral 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 participant receiving study product, barrier methods such as condoms with spermicide or diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill").
- •If participant 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.
- •Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product.
- •Participant Inclusion Criteria for Healthy Participants (Groups 1A-1C)
- •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 Institutional Review Board (IRB).
- •Agree to abide by the study restrictions.
- •Are healthy male or non-pregnant female, between the ages of 18 and 85 years, inclusive, with normal GFR >90 at screening.
- •Have no history of chronic tobacco/nicotine usage (i.e., >10 cigarettes per day for 3 months minimum prior to admission).
- •Have a normal corrected QT interval by Fridericia (QTcF) <460 msec on ECG.
- •Have a Body Mass Index of 18 to 40 kg/m^2 at enrollment.
- •Women of childbearing potential** must use an acceptable contraception method*** for the duration of the study.
- •**Not sterilized via tubal ligation, bilateral oophorectomy, bilateral 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 participant receiving study product, barrier methods such as condoms with spermicide or diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill").
- •If participant 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.
- •Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product.
排除标准
- •Participant Exclusion Criteria for Patients with Renal Impairment (Groups 2-4)
- •1. History of known active TB.
- •2. History of peptic ulcer disease.
- •3. 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 electrocardiogram (ECG) abnormality at screening\*.
- •\*Note: the following can be considered not clinically significant:
- •\- Heart rate \0.23 seconds)
- •* Right or left axis deviation
- •* Incomplete right bundle branch block
- •* Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic participants
- •6. History of, or screening results show a corrected QT interval by Fridericia (QTcF) \>/= 460 msec.
- •7. Family history of Long-QT Syndrome or sudden death when a cause of death is unknown.
- •8. Inability to swallow tablets.
- •9. History of fever or documented fever (oral temperature \>/= 100.4 degrees F) in the 48 hours prior to admission to the hospital.
- •10. Resting pulse rate \<50 or \>110 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.
- •12. Current hyperkalemia or hypomagnesemia.
- •13. Positive result of urine drug screen or blood alcohol screen prior to hospital admission except for approved prescriptions that are not opiates and benzodiazepines.
- •14. Significant history of drug and/or food allergies (as deemed by the Principal Investigator (PI)).
- •15. For women, participant is pregnant (positive test for urine Human Chorionic Gonadotropin \[HCG\]) at screening or Admission, breastfeeding, or planning to conceive for the duration of the study.
- •16. Any contraindication to the use of nitroimidazoles, or prior treatment with pretomanid or delamanid.
- •17. Treatment with strong or moderate CYP3A4 inducers or inhibitors\*\*\* within 14 days before admission and during the study\*\*\*\*.
- •\*\*\*Except hormonal contraceptives
- •\*\*\*\*In the opinion of the site investigator
- •18. Use of St. John's Wort within 7 days prior to admission and during the entire study.
- •19. Consumption of products containing grapefruit within 5 days prior to dosing until Visit 01N.
- •20. Donation of whole blood or blood products \>500 mL within 30 days from screening and/or plans to donate during the study or up to 14 days after dosing.
- •21. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit.
- •22. Hemoglobin (Hgb) \<8.0 g/dL in both men and women at the screening visit.
- •23. Positive Screening test for Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), or Human Immunodeficiency Virus (HIV).
- •24. Renal transplant.
- •25. Scheduled for hemodialysis or peritoneal dialysis.
- •26. Presence of any condition or finding\*\*\*\*\* which would jeopardize participant safety, impact study result validity, or diminish the participant's ability to undergo all study procedures and assessments.
- •\*\*\*\*\*In the opinion of the investigator
- •27. For men, semen donation for the duration of the study.
- •28. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) \> 2.5 x Upper Limit of Normal (ULN).
- •29. Hyperbilirubinemia \>1.5 x Upper Limits of Normal (ULN).
- •Participant Exclusion Criteria for Healthy Participants (Groups 1A-1C)
- •1. History of known active TB.
- •2. History of peptic ulcer disease.
- •3. 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 \0.23 seconds)
- •* Right or left axis deviation
- •* Incomplete right bundle branch block
- •* Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic participants
- 另有 24 项未显示
研究组 & 干预措施
Part A Group 1A
6 healthy participants with normal renal function: Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR > / = 90 mL/min) matched to Group 2 by race, gender, age (+/- 10 years, but between 18 to 85 years of age) and body mass index (BMI) (18 to 40 kg/m^2) will receive a single oral dose of 200 mg pretomanid
干预措施: PA-824 (Drug)
Part A Group 2
6 participants with severe renal impairment: Stage 4, Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR 15-29 mL/min), and 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) matched to Group 1A will receive a single oral dose of 200 mg pretomanid
干预措施: PA-824 (Drug)
Part B Group 1B
6 healthy participants with Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR of > / = 90 mL/min) matched to Group 3 by race, gender, age (+/- 10 years, but between 18 to 85 years of age) and body mass index (BMI) (18 to 40 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
干预措施: PA-824 (Drug)
Part B Group 1C
6 healthy participants: with Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR > / = 90 mL/min) matched to Group 4 by race, gender, age (+/- 10 years, but between 18 to 85 years of age) and body mass index (BMI) (18 to 40 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
干预措施: PA-824 (Drug)
Part B Group 3
6 participants with mild renal impairment: Stage 2, Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR 60-89 mL/min) 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
干预措施: PA-824 (Drug)
Part B Group 4
6 participants with moderate renal impairment: Stage 3, Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR = 30-59 mL/min) 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
干预措施: PA-824 (Drug)
结局指标
主要结局
Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls
时间窗: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
The mean fold change of 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. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site.
Fold Change in Pretomanid AUC(0-infinity) in Participants With Renal Impairment as Compared to Matched Healthy Controls
时间窗: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
The mean fold change of 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. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site.
次要结局
- Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points(Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.)
- Mean Change From Baseline in Alanine Aminotransferase (ALT)(Day 5 and Day 12)
- Mean Change From Baseline in Hemoglobin (Hgb)(Day 5 and Day 12)
- Mean Change From Baseline in Magnesium(Day 5 and Day 12)
- Mean Change From Baseline in Serum Potassium(Day 5 and Day 12)
- Mean Change in Oral Temperature From Baseline(Days 1, 2, 3, 4, 5, and 12)
- Mean Change in Pulse From Baseline(Days 1, 2, 3, 4, 5, and 12)
- Mean Change in Sitting Systolic Blood Pressure From Baseline(Days 1, 2, 3, 4, 5, and 12)
- Number of Participants With and Severity of Adverse Events(Day 1 to Day 85)
- Mean Change From Baseline in Aspartate Aminotransferase (AST)(Day 5 and Day 12)
- Mean Change From Baseline in Creatinine(Day 5 and Day 12)
- Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)(Day 5 and Day 12)
- Mean Change From Baseline in Total Bilirubin(Day 5 and Day 12)
- Mean Change in Sitting Diastolic Blood Pressure From Baseline(Days 1, 2, 3, 4, 5, and 12)
- Mean Change in the Electrocardiogram (ECG) Corrected QT Interval by Fridericia (QTcF) Interval From Baseline(Day 5)
- Mean Change From Baseline in Blood Urea Nitrogen (BUN)(Day 5 and Day 12)