Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pharmacokinetics of Polymyxin B in Adult Patients With Cystic Fibrosis

Conditions
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Cystic Fibrosis, Polymyxin B

Intervention / Treatment
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* Other: Blood Draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥ 18 years of age. Diagnosis of CF. Receiving polymyxin B in the course of routine care. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with CF lung disease receiving Polymyxin B (PMB)<br>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<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 |