Clinical trial NCT04178577: Phase 1 Study of PK and Safety of Tebipenem Pivoxil Hydrobromide (TBPM-PI-HBr) in Subjects With Various Degrees Of Renal Function
Official title: A Phase 1, Open-Label Study to Assess the Pharmacokinetics and Safety of Orally Administered Tebipenem Pivoxil Hydrobromide (TBPM-PI-HBr) in Subjects With Various Degrees of Renal Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Keywords: End State Renal Disease (ESRD)
Renal Insufficiency
Renal Impairment
Renal Disease
Hemodialysis
Lead sponsor: Spero Therapeutics
Sponsor class: INDUSTRY
First posted: 2019-11-26
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility 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.

Primary outcomes:
measure: Apparent total body clearance (CL/F).
timeFrame: 72 hours post dose
measure: Area under the curve from time zero to the last quantifiable sample (AUC0-last).
timeFrame: 72 hours post dose
measure: Area under the curve extrapolated to infinity (AUC0-∞).
timeFrame: 72 hours post dose
measure: Apparent steadystate volume of distribution (Vss/F).
timeFrame: 72 hours post dose
measure: Maximum plasma concentration (Cmax).
timeFrame: 72 hours post dose
measure: Time to the maximum plasma concentration (Tmax).
timeFrame: 72 hours post dose
measure: Terminal elimination half-life (t1/2).
timeFrame: 72 hours post dose
Secondary outcomes:
measure: Incidence of treatment-emergent AEs (including SAEs) categorized by severity and relationship to study drug.
timeFrame: 14 days post last dose
measure: Significant changes from baseline in clinical laboratory values.
timeFrame: 14 days post last dose
measure: Significant changes from baseline in physical examination.
timeFrame: 14 days post last dose
measure: Significant changes from baseline in vitals signs.
timeFrame: 14 days post last dose
measure: Significant changes from baseline in ECG
timeFrame: 14 days post last dose
measure: Renal clearance (CLR)
timeFrame: 72 hours post dose
measure: Fraction of drug excreted in the urine expressed as a percentage of the TBPM-PI-HBr dose administered (Ae%).
timeFrame: 72 hours post dose
measure: 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.
timeFrame: 72 hours post dose
measure: For subjects on dialysis, estimated hemodialysis clearance (CLHD) will be assessed.
timeFrame: Up to 1 day post dose - between start and end of hemodialysis.
measure: For subjects on dialysis, the extraction ratio (ER) will be assessed.
timeFrame: Up to 1 day post dose - between start and end of hemodialysis.
measure: For subjects on dialysis, the amount of the dose removed by hemodialysis (XHD) will be assessed.
timeFrame: Up to 1 day post dose - between start and end of hemodialysis.
Other outcomes:
measure: For subject in Cohort 1, cumulative amount of TBPM metabolite excreted in urine.
timeFrame: 72 hours post dose
measure: For subjects in Cohort 1, cumulative urinary excretion of TBPM and TBPM metabolite as a % of dose administered.
timeFrame: 72 hours post dose
Locations:
city: Miami
country: United States
facility: Medical Facility
state: Florida
city: Orlando
country: United States
facility: Medical Facility
state: Florida
Study officials:
affiliation: Spero Therapeutics Inc
name: David Melnick, M.D.
role: STUDY_DIRECTOR
References:
citation: Patel G, Rodvold KA, Gupta VK, Bruss J, Gasink L, Bajraktari F, Lei Y, Jain A, Srivastava P, Talley AK. Pharmacokinetics of Oral Tebipenem Pivoxil Hydrobromide in Subjects with Various Degrees of Renal Impairment. Antimicrob Agents Chemother. 2022 May 17;66(5):e0240721. doi: 10.1128/aac.02407-21. Epub 2022 Apr 14.