Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis

Cystic Fibrosis Clinical Trial

Official title:

Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04335370
• Other study ID #: HUM00150013
• Status: Completed
• Start date: January 9, 2019
• Est. completion date: July 1, 2021

Study information

• Verified date: July 2023
• Source: University of Michigan
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

This study initially planned to include "Change in forced expiratory volume in one second (FEV1)" and "Non-response to therapy" as secondary outcome measures. These outcome measures were removed, as the small number of participants prohibited collection of significant data beyond what was collected for the baseline measures.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: July 1, 2021
• Est. primary completion date: July 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Adults = 18 years of age.

2. Diagnosis of CF.

3. Receiving polymyxin B in the course of routine care.

Exclusion Criteria:

1. Evidence of acute kidney injury during the 48 hours prior to and following initiation of PMB therapy.

2. Extracorporeal organ support (including ECMO, iHD, and CRRT).

3. Pregnant or breastfeeding women.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Polymyxin B

Intervention

Other:
• Blood Draw
Blood samples will be collected from enrolled patients at 5 time points during a single dosing interval: Prior to start of infusion End of infusion One hour after end of infusion Three hours after end of infusion Eight hours after start of infusion

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
University of Michigan	Cystic Fibrosis Foundation

Country where clinical trial is conducted

United States, 

References & 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Acute kidney injury	Frequency of acute kidney injury occurring between 48 hours after initiation of polymyxin B and 48 hours after end of therapy	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
Secondary	Neurotoxicity	Frequency of neurotoxicities occurring during polymyxin B treatment as documented by the primary clinical team	From initiation of first dose through end of therapy, approximately 7-21 days depending on the length of the prescribed therapy
Secondary	Change in forced expiratory volume in one second (FEV1)	After completion of polymyxin B therapy as documented by the primary clinical team	FEV1 at baseline to 7 days post treatment, approximately 14-90 days in total
Secondary	Non-reponse to therapy	Proportion of subjects requiring a change to antibiotic therapy due to non-response as documented by the primary clinical team	From initiation of therapy through end of therapy, approximately 7-21 days depending on prescribed length of therapy