Clinical trial NCT04335370: Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis
Official title: Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cystic Fibrosis
Polymyxin B
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: Cystic Fibrosis Foundation
First posted: 2020-04-06
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: CF patients admitted to the University of Michigan hospitals requiring polymyxin B as part of clinical care

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Polymyxin B compartmental population pharmacokinetics model
timeFrame: From immediately prior to a dose of therapy through 8 hours after therapy, approximately 8 hours
Secondary outcomes:
measure: Acute kidney injury
timeFrame: 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
measure: Neurotoxicity
timeFrame: From initiation of first dose through end of therapy, approximately 7-21 days depending on the length of the prescribed therapy
measure: Change in forced expiratory volume in one second (FEV1)
timeFrame: FEV1 at baseline to 7 days post treatment, approximately 14-90 days in total
measure: Non-reponse to therapy
timeFrame: From initiation of therapy through end of therapy, approximately 7-21 days depending on prescribed length of therapy
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: Shijing Jia
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.