Ruth Van Daele1, Roger J Brüggemann2, Erwin Dreesen3, Pieter Depuydt4, Bart Rijnders5, Frédéric Cotton6, David Fage6, Matthias Gijsen1, Kenny Van Zwam7, Yves Debaveye8, Joost Wauters9, Isabel Spriet1. 1. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and Pharmacy Department, University Hospitals Leuven, Leuven, Belgium. 2. Department of Pharmacy and Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen and Center of Expertise in Mycology Radboudumc/CWZ, Radboud University Medical Center, Nijmegen, The Netherlands. 3. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 4. Department of Intensive Care, Ghent University Hospital, Ghent, Belgium. 5. Department of Infectious Diseases, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands. 6. Department of Clinical Chemistry, LHUB-ULB, Erasme Hospital and, Université Libre de Bruxelles, Bruxelles, Belgium. 7. Department of Perfusion, University Hospitals Leuven, Leuven, Belgium. 8. Intensive Care Unit, University Hospitals Leuven and Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. 9. Medical Intensive Care Unit, University Hospitals Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
Abstract
BACKGROUND: Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically ill patients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO. OBJECTIVES: To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA. METHODS: Critically ill patients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2-3) and a late (Day 4-7) sampling day. Daily trough concentrations were measured. RESULTS: The median (IQR) AUC0-24, CL and Vd were 34.3 (28.3-37.7) mg·h/L, 8.7 (8.0-10.6) L/h and 389 (314-740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment. CONCLUSIONS: ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.
BACKGROUND:Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically illpatients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO. OBJECTIVES: To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA. METHODS:Critically illpatients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2-3) and a late (Day 4-7) sampling day. Daily trough concentrations were measured. RESULTS: The median (IQR) AUC0-24, CL and Vd were 34.3 (28.3-37.7) mg·h/L, 8.7 (8.0-10.6) L/h and 389 (314-740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment. CONCLUSIONS: ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.
Authors: Paul E Verweij; Roger J M Brüggemann; Elie Azoulay; Matteo Bassetti; Stijn Blot; Jochem B Buil; Thierry Calandra; Tom Chiller; Cornelius J Clancy; Oliver A Cornely; Pieter Depuydt; Philipp Koehler; Katrien Lagrou; Dylan de Lange; Cornelia Lass-Flörl; Russell E Lewis; Olivier Lortholary; Peter-Wei Lun Liu; Johan Maertens; M Hong Nguyen; Thomas F Patterson; Bart J A Rijnders; Alejandro Rodriguez; Thomas R Rogers; Jeroen A Schouten; Joost Wauters; Frank L van de Veerdonk; Ignacio Martin-Loeches Journal: Intensive Care Med Date: 2021-06-23 Impact factor: 17.440