A Pharmacokinetic Study of Polymyxin B in Healthy Subjects and Subjects With Renal Insufficiency

NCT05359627 | Completed Phase 1

• 1 other identifier: TTYPX2201
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single-center, single-dose, parallel-group study to evaluate the PK and safety profiles of polymyxin B administered by IV infusion in healthy subjects and subjects with renal insufficiency.

Conditions

Antibiotic Toxicity

Outcome Measures

Primary Outcomes (4)

• Cmax

  Cmax: Maximum observed plasma concentration

  Baseline,48hours

• AUC0-last

  AUC0-last: Area under the plasma concentration vs time curve from time 0 to the last measurable concentration

  Baseline,48hours

• AUC0-inf

  AUC0-inf: Area under the plasma concentration vs time curve from time 0 extrapolated to infinity

  Baseline,48hours

• CL

  CL: Clearance, calculated as Dose/AUC0-inf

  Baseline,48hours

Study Arms (3)

Arm 1

EXPERIMENTAL

normal renal function group

Drug: Polymyxin B

Arm 2

EXPERIMENTAL

mild renal insufficiency group

Drug: Polymyxin B

Arm 3

EXPERIMENTAL

long-term IHD group

Drug: Polymyxin B

Interventions

Polymyxin B DRUG

Polymyxin B acts against gram-negative bacteria (GNB) only, via three known mechanisms of action: First, polymyxin B can electrostatically interact with the outer membranes of GNB to compete against and displace calcium and magnesium divalent cations from membrane lipids, thereby disrupting lipopolysaccharide (LPS) molecules on the outer membrane and triggering their release. This leads to changes in the permeability of the bacterial membrane and subsequently causes cell content leakage, cell lysis, and death. Second, polymyxin B can act as a surfactant, as it is amphipathic and contains both lipophilic and lipophobic groups; this allows it to penetrate cell membranes, interact with the phospholipids within, and rapidly disrupt membranes to kill bacteria. Third, polymyxin B can bind to the lipid A portion of bacterial endotoxin or LPS molecules, thus neutralizing their toxicity.

Arm 1; Arm 2; Arm 3

Eligibility Criteria

• Age: 20 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female subjects between 20 and 70 years of age (inclusive) at screening.
• Subjects with Body Mass Index (BMI) between 18.5 and 35 kg/m² (inclusive) at screening.
• Subjects with sitting heart rate between 60 and 100 beats/min at screening.
• Subjects with serum albumin between 3.5 and 5.7 g/dL (inclusive).
• Subjects (normal renal function group) with creatinine clearance (CLcr) ≥ 90 mL/min at screening; Subjects (mild renal insufficiency group) with CLcr between 60 and 89 mL/min (inclusive) within 3 months prior to screening and at screening; Subjects (long-term IHD group) with ESRD receiving IHD therapy 3 times a week for at least 3 months prior to dosing of study drug.
• Female subjects with childbearing potential must have a negative serum pregnancy test at screening and pregnancy test on Day -1.
• Subjects with sufficient peripheral vascular access for blood collection.
• Subject is willing and able to comply with all study procedures and restrictions.
• Subject understands the study procedures and is willing and able to provide written informed consent.

You may not qualify if:

• Arm 1 (normal renal function group): Subject with history or presence of any clinically significant cardiovascular, respiratory, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, psychiatric disease or disorder, with active bleeding or with head injury or meningitis 3 months prior to dosing, in the opinion of the investigator or any uncontrolled medical illness which in the opinion of the investigator would jeopardize the safety of the subject, interfere with study assessments, or impact the validity of the study results; Arm 2 (mild renal insufficiency group): Subject with history or presence of any clinically significant cardiovascular, respiratory, hepatic, hematological, immunologic, neurological, psychiatric disease, active bleeding within 3 months, congenital renal disease (e.g., polycystic kidney disease) or disorder, with head injury or meningitis 3 months prior to dosing, in the opinion of the investigator or any uncontrolled medical illness which in the opinion of the investigator would jeopardize the safety of the subject, interfere with study assessments, or impact the validity of the study results; Arm 3 (long-term IHD group): Subject with history or presence of any clinically significant respiratory, hepatic, hematological, immunologic, neurological, psychiatric disease, active bleeding within 3 months, congenital renal disease (e.g., polycystic kidney disease) or disorder, with head injury or meningitis 3 months prior to dosing, in the opinion of the investigator or any uncontrolled medical illness which in the opinion of the investigator would jeopardize the safety of the subject, interfere with study assessments, or impact the validity of the study results.
• Known history of or positive screening result for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (HCVAb).
• Subject has a positive test result for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral RNA test on Day -1.
• Subject who has a known, or suspected allergy, or sensitivity to polymyxins (colistin, polymyxin B) antibiotics in the opinion of the investigator.
• Subject with current evidence or history of malignancy in the 1 year prior to Day -1.
• Subject who has received polymyxins (colistin, polymyxin B) treatment within 28 days prior to Day -1.
• Use of prohibited medications of this study within 28 days (or 5 half-lives, if longer) prior to Day -1.
• Subjects with a QT interval corrected using Fridericia's formula (QTcF) prolongation over 500 milliseconds or history of prolonged QT syndrome at screening.
• Subject who used other investigational medicine within 28 days prior to the screening visit or plan to use other investigational medicine during the study period.
• Donation of blood within 56 days or plasma within 14 days prior to the screening visit or plan to donate during the entire study period.
• Blood transfusion within 14 days prior to the screening visit or necessary for regular blood transfusion within 3 months prior to the screening visit.
• Reports of a history of substance or alcohol abuse within 1 year prior to the screening visit.
• Female subject who is currently pregnant or breastfeeding or plans to be pregnant during the study period.
• Unstable or new medical conditions in the 3 months prior to screening.
• Any condition determined by the investigator to be unsuitable for subject enrollment.

Sponsors & Collaborators

• TTY Biopharm: lead

Study Sites (1)

Shin Kong Memorial Wu Ho-Su Hospital

Taipei, Taiwan

Location

MeSH Terms

Interventions

Polymyxin B

Intervention Hierarchy (Ancestors)

Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins

Study Officials

• Fang

  Shin Kong Memorial Wu Ho-Su Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2022
• First Posted: May 4, 2022
• Study Start: July 26, 2022
• Primary Completion: March 3, 2023
• Study Completion: March 3, 2023
• Last Updated: April 27, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)