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
Overview
- Phase
- Phase 1
- Intervention
- PA-824
- Conditions
- Renal Impairment
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 12
- Locations
- 3
- Primary Endpoint
- Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •Participant Exclusion Criteria for Patients with Renal Impairment (Groups 2-4)
- •History of known active TB.
- •History of peptic ulcer disease.
- •Known hypersensitivity to pretomanid or any of the excipients.
- •History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI)).
- •Any clinically significant electrocardiogram (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 participants, as determined by the Principal Investigator ))
- •Mild first-degree atrioventricular (A-V) block (P-R interval \>0.23 seconds)
- •Right or left axis deviation
Arms & Interventions
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
Intervention: PA-824
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
Intervention: PA-824
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
Intervention: PA-824
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
Intervention: PA-824
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
Intervention: PA-824
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
Intervention: PA-824
Outcomes
Primary Outcomes
Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls
Time Frame: 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
Time Frame: 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.
Secondary Outcomes
- 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)