Changes of colistin pharmacokinetics in critically ill patients due to the extracorporeal membrane oxygenation: protocol for the COL-ECMO2022 trial – a prospective, non-randomised, open-label phase IV pharmacokinetic clinical trial

Abstract

IntroductionColistin is a lipopeptide antibiotic administered as an inactive prodrug—colistin methanesulfonate (CMS). Colistin is a drug with a narrow therapeutic window; the limiting factors are mainly nephrotoxicity and neurotoxicity, dependent on plasma concentrations. The number of patients with infections caused by multidrug-resistant Gram-negative bacteria sensitive only to colistin and the number of patients requiring extracorporeal membrane oxygenation (ECMO) support for severe respiratory failure increased significantly in association with COVID-19-induced infections. ECMO can generally affect the pharmacokinetics of drugs by creating a new compartment.Methods and analysisThe COL-ECMO2022 study is a prospective, non-randomised, single-centre, phase IV pharmacokinetic clinical trial designed to assess the influence of ECMO on the pharmacokinetics of colistin and CMS. Up to 30 patients treated with colistin will be included in the study and assigned to one of two arms, depending on the presence/absence of ECMO. All study participants will receive standard CMS dose intravenously. The plasma concentrations of colistin and CMS taken at defined intervals will be assessed by high-performance liquid chromatography-mass spectrometry. Patients will participate in the clinical trial for a maximum of three monitored dosing intervals. A population pharmacokinetic model will be developed to assess the influence of ECMO on pharmacokinetics. A difference greater than 25% is considered clinically significant.Ethics and disseminationThe study has been approved by the Ethics Committee of St. Anne’s University Hospital Brno (Number 10ML/2022-AM). Related manuscripts will be submitted to peer-review journals.Trial registration numbersEudraCT Number 2022-000291-19;NCT05542446.