Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis

Completed

• Conditions: Cystic Fibrosis; Polymyxin B
• Interventions: Other: Blood Draw

• Registration Number: NCT04335370
• Lead Sponsor: University of Michigan

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.

Detailed 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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2019-01-09
• Study First Submitted: 2020-04-02
• Study First Submitted QC: 2020-04-02
• Study First Posted: 2020-04-06
• Primary Completion: 2021-07-01
• Study Completion: 2021-07-01
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-24
• Last Update Posted: 2023-07-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 9

Inclusion Criteria

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

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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.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients with CF lung disease receiving Polymyxin B (PMB)	Blood Draw	Participants receiving polymyxcin B as part of standard of care treatment for CF exacerbation will have blood drawn measure blood concentrations of PMB

Primary Outcome Measures

Name	Time	Method
Polymyxin B compartmental population pharmacokinetics model	From immediately prior to a dose of therapy through 8 hours after therapy, approximately 8 hours	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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States