Renal Impairment
Conditions
Keywords
End State Renal Disease (ESRD), Renal Insufficiency, Renal Impairment, Renal Disease, Hemodialysis
Brief summary
Evaluation of the pharmacokinetics (PK) of TBPM-PI-HBr in subjects with normal renal function, subjects with various degrees of renal insufficiency, and subjects with end-stage renal disease (ESRD) receiving hemodialysis (HD) therapy.
Interventions
Tebipenem pivoxil hydrobromide (TBPM-PI-HBr) 600 mg single-dose given orally.
Sponsors
Spero Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Adult males or females, 18 years of age or older. * BMI ≥ 18.5 and ≤ 39.9 (kg/m2) and weight between 50.0 and 130.0 kg * Medically healthy without clinically significant abnormalities (Healthy Volunteers) or medically stable without clinically significant acute or chronic illness (Subjects with Renal Disease). * Non-smoker for at least 1 month prior to screening for the study. * Ability and willingness to abstain from alcohol, caffeine, xanthinecontaining beverages or food. Key
Exclusion criteria
* Any clinically significant medical history or abnormal findings upon physical examination, or clinical laboratory tests, not specifically excluded in other criteria below that, in the opinion of the Investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. * Electrocardiogram (ECG) with QTcF interval duration equal or greater than 500 msec * Hemoglobin (HB), hematocrit (HCT), white blood cell count (WBC), or platelet count less than the lower limit of normal range of the reference laboratory (Cohort 1). HB \< 8.5 gm/dL, WBC ≤ 3,000 cells/μL or platelet count ≤ 100,000 cells/μL (Cohorts 2-5). * Results of biochemistry tests for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin greater than 1.5 X the upper limit of normal (ULN) for the reference laboratory. * Recent history of known or suspected Clostridium difficile infection. * History of known genetic metabolism anomaly associated with carnitine deficiency (e.g., carnitine transporter defect, methylmalonic aciduria, propionic academia). * History of chronic liver disease, cirrhosis, or biliary disease. * History of seizure disorder except childhood history of febrile seizures. * Positive urine drug/alcohol testing. * Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C (HCV) antibodies. * History of substance abuse or alcohol abuse. * Use of antacids within 24 hours prior to study drug administration. * Known history of clinically significant hypersensitivity reaction or anaphylaxis to any medication.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Terminal elimination half-life (t1/2). | 72 hours post dose |
| Time to the maximum plasma concentration (Tmax). | 72 hours post dose |
| Apparent total body clearance (CL/F). | 72 hours post dose |
| Area under the curve from time zero to the last quantifiable sample (AUC0-last). | 72 hours post dose |
| Area under the curve extrapolated to infinity (AUC0-∞). | 72 hours post dose |
| Apparent steadystate volume of distribution (Vss/F). | 72 hours post dose |
| Maximum plasma concentration (Cmax). | 72 hours post dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fraction of drug excreted in the urine expressed as a percentage of the TBPM-PI-HBr dose administered (Ae%). | 72 hours post dose | — |
| Amount of drug excreted in the urine through 24 hours (Ae0-24), through 48 hours (Ae0-48) and through 72 hours (Ae0-72) for Cohorts 1-4. | 72 hours post dose | — |
| For subjects on dialysis, the extraction ratio (ER) will be assessed. | Up to 1 day post dose - between start and end of hemodialysis. | — |
| For subjects on dialysis, the amount of the dose removed by hemodialysis (XHD) will be assessed. | Up to 1 day post dose - between start and end of hemodialysis. | — |
| For subjects on dialysis, estimated hemodialysis clearance (CLHD) will be assessed. | Up to 1 day post dose - between start and end of hemodialysis. | — |
| Incidence of treatment-emergent AEs (including SAEs) categorized by severity and relationship to study drug. | 14 days post last dose | AEs will be categorized by system organ class (SOC) and AE preferred term (PT). |
| Significant changes from baseline in clinical laboratory values. | 14 days post last dose | All laboratory data will be summarized by cohort, and at each scheduled time-point using descriptive statistics (n, mean, SD, median, minimum, and maximum). E.g. of laboratory values: hematology, biochemistry, coagulation and urinalysis |
| Significant changes from baseline in physical examination. | 14 days post last dose | Changes in baseline in physical examination findings (Normal, Abnormal NCS, Abnormal CS) will be summarized using counts and percentages by cohort, and will also be listed individually for each scheduled time-point. Physical examination will include: HEENT; cardiovascular, respiratory, gastrointestinal, dermatological, musculoskeletal, nervous systems, lymph nodes and general appearance. Additional body systems may be evaluated at the Investigator's discretion. |
| Significant changes from baseline in vitals signs. | 14 days post last dose | Vital sign values and changes from baseline at each scheduled time-point will be summarized by cohort for the Safety Analysis Population using descriptive statistics (n, mean, SD, median, minimum, and maximum). Vitals signs will include: systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. |
| Significant changes from baseline in ECG | 14 days post last dose | Overall evaluation of safety ECGs will be summarized by cohort, using frequency counts and percentage of subjects as normal or abnormal, and the relevance of the abnormality will be summarized by CS or NCS. ECG parameters will include: heart rate, RR interval, PR interval, QRS, QT and QTcF |
| Renal clearance (CLR) | 72 hours post dose | — |
Other
| Measure | Time frame |
|---|---|
| For subject in Cohort 1, cumulative amount of TBPM metabolite excreted in urine. | 72 hours post dose |
| For subjects in Cohort 1, cumulative urinary excretion of TBPM and TBPM metabolite as a % of dose administered. | 72 hours post dose |
Countries
United States
Outcome results
None listed