Pharmacokinetics of Voriconazole in Adult ECMO Patients

Study Overview
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Brief Summary
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Given the high burden of fungal co-infection in patients admitted to ICU and improved outcomes with prompt anti-fungal treatment, it is of vital importance that the doses of anti-fungal are optimum to improve the dismal outcome of influenza/Covid-19 Associated Pulmonary Aspergillosis. Due to the reported difficulties in dosing appropriately in ECMO patients, a prospective observational study is required to accurately evaluate the pharmacokinetics of voriconazole in patients supported on ECMO. This is to ensure that the dose of voriconazole is optimised to improve efficacy and reduce toxicity.

Detailed Description
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A single centre, open label, prospective, observational, pharmacokinetic study of voriconazole administered to adults (aged > 18 years) supported on ECMO. This is a low-interventional study. There will be no treatment changes as a result of participation in this study. The decision to initiate voriconazole therapy will be taken independent of this study protocol. Intravenous voriconazole will be prescribed according to the approved dose in the SmPC. All adults requiring voriconazole therapy will be eligible for recruitment into the study. The only additional procedure in this study will be to take a total of 5 blood samples across 3 occasions/sampling windows (Day 1-4, Day 6-9 and Day 11-14) to determine plasma concentrations of voriconazole. In addition, a single buccal swab to determine the CYP2C19 genotype will be undertaken during the course of ICU stay.

Official Title
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An Observational Pharmacokinetic Study of Intravenous Voriconazole Used for Treatment of Invasive Aspergillosis in Adult Patients With Severe Influenza / COVID-19 Supported With Extra-corporeal Membrane Oxygenation (ECMO)

Conditions
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Covid19, Aspergillosis, Influenza

Intervention / Treatment
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* Other: 5 blood samples
* Genetic: Determination of CYP2C19 genotype


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged ≥18 years Admitted to ICU on ECMO support Positive influenza or SARS-CoV-2 PCR from nasal, throat swab, BAL or other respiratory specimen. Positive invasive aspergillosis infection (positive Aspergillus species culture from respiratory specimen or positive serum galactomannan) or strong clinical suspicion of invasive aspergillosis infection based on symptoms, CT, CXR. Exclusion Criteria: No participants < 18 years of age Not requiring ECMO support No positive influenza or SARS-CoV-2 results Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.

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 |
| --- | --- |
| Voriconazole administration to adult patients with suspected fungal disease, receiving ECMO support<br>Adult (>18 years) patients with severe influenza / Covid-19 supported on ECMO and with confirmed or suspected aspergillosis infection. | Other: 5 blood samples<br>* 5 blood samples across 3 occasions/sampling windows (Day 1-4, Day 6-9 and Day 11-14) to determine plasma concentrations of voriconazole<br>Genetic: Determination of CYP2C19 genotype<br>* A single buccal swab to determine the CYP2C19 genotype will be undertaken during the course of ICU stay.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support. | Primary parameter: Clearance (CL) | 14 days | 
| Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support. | Primary parameter: Volume of distribution (V) | 14 days | 
| Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support. | Secondary parameters: Maximum plasma concentration (Cmax) | 14 days | 
| Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support. | Secondary parameters: Area under plasma concentration time curve (AUC) | 14 days | 
| Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support. | Secondary parameters: Half-life (t1/2) | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the influence of CYP2C19 genotype on the plasma levels of voriconazole | CYP2C19 genotype: identify *2, *3, and *17 mutations and any influence on plasma levels of voriconazole | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Voriconazole, Extracorporeal Membrane Oxygenation