Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis

NCT04335370 | Completed

• 1 other identifier: HUM00150013
• Study Type: observational
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Cystic fibrosis (CF) pulmonary disease is a major cause of morbidity and mortality in CF patients and is punctuated by episodes of acute exacerbation that require antibiotic treatment. Pseudomonas aeruginosa is the predominant bacterial pathogen isolated in patients with acute exacerbations, and practice guidelines recommend combination antibiotics directed against this pathogen as initial therapy. Such therapy traditionally consists of an antipseudomonal beta-lactam with either an antipseudomonal fluoroquinolone or an aminoglycoside. With growing P. aeruginosa multi-drug resistance, more adult patients present with isolates resistant to these traditional options. The polymyxins are a class of cyclic peptide antibiotics that exert bactericidal activity through binding to the lipopolysaccharide component of gram-negative bacterial membranes and include colistin and polymyxin B (PMB). In recent years, there is growing evidence of increased rates of acute kidney injury associated with colistin in critically ill patients. Additionally, population pharmacokinetic (PK) studies suggest that fixed drug dosing may yield an improved therapeutic index over the traditional weight-based dosing of this agent. Thus there is growing interest in use of PMB as an alternative in CF acute exacerbations but the optimal dosage regimen is not known. This is a single-center, open-label, non-interventional study to characterize the pharmacokinetics and safety of fixed-dose PMB in adult patients with CF by measuring serum concentrations in patients receiving IV therapy as a part of routine care. This study will help to validate existing population PK models and allow for adjustment of patient specific covariates (i.e. weight, renal function) unique to adult patients with CF. The study will also monitor for nephrotoxicity and neurotoxicity to determine if PMB has an acceptable margin of safety in this patient population. This investigation is the first to prospectively validate the pharmacokinetics and toxicities of fixed-dose PMB in CF and will guide optimal use of this compound in the management of acute pulmonary exacerbations.

Conditions

Cystic Fibrosis; Polymyxin B

Outcome Measures

Primary Outcomes (1)

• Polymyxin B compartmental population pharmacokinetics model

  The population pharmacokinetics of polymyxin B will be modeled based on the observed polymyxin B1 and B2 concentrations in plasma from enrolled patients who receive at least 1 dose of polymyxin B

  From immediately prior to a dose of therapy through 8 hours after therapy, approximately 8 hours

Secondary Outcomes (4)

• Acute kidney injury

  From 48 hours after first dose through 48 hours after end of therapy, approximately 7-21 days depending on the length of the prescribed therapy

• Neurotoxicity

  From initiation of first dose through end of therapy, approximately 7-21 days depending on the length of the prescribed therapy

• Change in forced expiratory volume in one second (FEV1)

  FEV1 at baseline to 7 days post treatment, approximately 14-90 days in total

• Non-reponse to therapy

  From initiation of therapy through end of therapy, approximately 7-21 days depending on prescribed length of therapy

Study Arms (1)

Patients with CF lung disease receiving Polymyxin B (PMB)

Participants receiving polymyxcin B as part of standard of care treatment for CF exacerbation will have blood drawn measure blood concentrations of PMB

Other: Blood Draw

Interventions

Blood Draw OTHER

Blood samples will be collected from enrolled patients at 5 time points during a single dosing interval: 1. Prior to start of infusion 2. End of infusion 3. One hour after end of infusion 4. Three hours after end of infusion 5. Eight hours after start of infusion

Patients with CF lung disease receiving Polymyxin B (PMB)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

CF patients admitted to the University of Michigan hospitals requiring polymyxin B as part of clinical care

You may qualify if:

• Adults ≥ 18 years of age.
• Diagnosis of CF.
• Receiving polymyxin B in the course of routine care.

You may not qualify if:

• Evidence of acute kidney injury during the 48 hours prior to and following initiation of PMB therapy.
• Extracorporeal organ support (including ECMO, iHD, and CRRT).
• Pregnant or breastfeeding women.

Sponsors & Collaborators

• University of Michigan: lead
• Cystic Fibrosis Foundation: collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (1)

• Crass RL, Al Naimi T, Wen B, Souza E, Murray S, Pai MP, Jia S. Pharmacokinetics of Polymyxin B in Hospitalized Adults with Cystic Fibrosis. Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0079221. doi: 10.1128/AAC.00792-21. Epub 2021 Jul 12.

  PMID: 34252297 RESULT

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Shijing Jia

  University of Michigan

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Internal Medicine

Study Record Dates

• First Submitted: April 2, 2020
• First Posted: April 6, 2020
• Study Start: January 9, 2019
• Primary Completion: July 1, 2021
• Study Completion: July 1, 2021
• Last Updated: July 25, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)