Pharmacokinetics of Isavuconazole in Patients in the Intensive Care Unit (ICONIC)

Pharmacokinetics of Isavuconazole (Cresemba®) Given as Treatment of Invasive Fungal Infections in Patients in the Intensive Care Unit

20 patients admitted to the ICU department and receiving isavuconazole as part of standard care for the treatment of fungal infections will be included in the study. Between day 3 and 7, 8 samples will be collected at t = 0 (pre-dose), and t = 0.5, 1, 2, 4, 6, 8 and 12 hours after end of infusion to obtain a PK curve. An optional, additional sample can be collected after discontinuation of isavuconazole therapy if possible. Total and free isavuconazole concentrations will be determined. A pharmacokinetic model will be fitted to the data from all individuals simultaneously. Data will be analysed using non-linear mixed effects modelling (NONMEM).

Study Overview

• Status: Completed
• Conditions: Invasive Fungal Infections; Pharmacokinetics; Intensive Care Unit

Detailed Description

Fungal infections are a serious threat to immunocompromised patients and represent a major burden in the critical care setting. The azole antifungal drugs are the most important drugs for managing infections caused by Aspergillus moulds and the prevention of invasive fungal infections in general. Azoles are currently used as first line prophylaxis and treatment of invasive aspergillosis and their use has substantially improved the survival of the overall population. Recently, there has been increased awareness for invasive aspergillosis cases in critically ill patients, including patients with severe influenza (influenza associated pulmonary aspergillosis, IAPA), and recently COVID-19 associated pulmonary aspergillosis (CAPA). These patients require azole-based therapy, for which voriconazole and isavuconazole are recommended first choice drugs.

Isavuconazole is a relatively novel azole drug with promising efficacy, a broad antifungal spectrum, favourable side effect profile and limited drug-drug interactions compared to other azole agents. Isavuconazole is registered for the primary treatment of adults with invasive aspergillosis, and patients with mucormycosis where amphotericin B is not suitable. Efficacy and safety information in the isavuconazole label is mostly derived from clinical studies in healthy volunteers. However, the pharmacokinetics in some specific patient populations may differ greatly from those in the healthy population. Changes in pharmacokinetics of isavuconazole in ICU patients are to be expected due to a wide variety of factors, e.g. changes in protein binding and changes in fluid distribution. Therefore, it is likely that the present standard dosing regimens of isavuconazole lead to suboptimal outcomes for ICU patients, similar to observations made for fluconazole and echinocandins. Optimizing dosing regimens in ICU patients for existing antifungal agents such as isavuconazole is important to improve clinical outcome rates. To date, limited information on the pharmacokinetics of isavuconazole in critically ill patients is available and optimal dosing regimens remain uncertain. With this study we aim to describe isavuconazole pharmacokinetics in ICU admitted patients.

20 patients admitted to the ICU department and receiving isavuconazole as part of standard care for the treatment of fungal infections will be included in the study. Between day 3 and 7, 8 samples will be collected at t = 0 (pre-dose), and t = 0.5, 1, 2, 4, 6, 8 and 12 hours after end of infusion to obtain a PK curve. An optional, additional sample can be collected after discontinuation of isavuconazole therapy if possible. Total and free isavuconazole concentrations will be determined. A pharmacokinetic model will be fitted to the data from all individuals simultaneously. Data will be analysed using non-linear mixed effects modelling (NONMEM). NONMEM is a one-stage analysis that simultaneously estimates mean parameters, fixed effect parameters, interindividual variability, and residual random effects. Since allowance can be made for individual differences, this method can be used with both intensive sampling and sparse data (and in the occasion of missing values: an unbalanced number of data points per patients).

Primary objective:

• To determine the pharmacokinetics of isavuconazole given as treatment of invasive fungal infections in ICU patients as part of standard care.

Secondary objectives:

• To investigate the protein binding of isavuconazole in ICU patients and the variability in protein binding between patients in the ICU population.
• To explore if unbound isavuconazole concentrations can be predicted from total isavuconazole concentrations.
• To assess pharmacokinetic/pharmacodynamic target attainment in the ICU patient population.

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • University Hospitals Leuven
• Netherlands
  • Den Bosch, Netherlands
    • Jeroen Bosch Hospital
  • Nijmegen, Netherlands
    • Radboud University Medical Centre
  • Utrecht, Netherlands
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Twenty ICU patients treated with isavuconazole for a fungal infection are eligible for inclusion. These patients are admitted to the ICU of Radboudumc and UZ Leuven. Since the objective is to evaluate the pharmacokinetics of isavuconazole in a real-life cohort of patients admitted to the ICU, exclusion criteria are minimal on purpose, to give a good reflection of this heterogenic cohort. The possible inclusion of patients with for example hepatic insufficiencies, continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO) et cetera, is considered. High variability between subjects in this highly heterogenetic patient population is expected and will be considered in the analyses.

Description

Inclusion Criteria:

• Patient is admitted to an ICU
• Is treated with isavuconazole intravenously (iv)
• Subject is at least 18 years on the day of the first dosing
• Is managed with a central venous catheter or arterial line

Exclusion Criteria:

• Patient has previously participated in this study

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients; Patients admitted to the intensive care unit, treated with isavuconazole intravenously for treatment of invasive fungal infections

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Isavuconazole clearance in ICU patients.	Isavuconazole clearance in ICU patients in liters/hour. Full pharmacokinetic curves will be taken and an optional sample during the elimination phase of isavuconazole.	Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Isavuconazole volume of distribution in ICU patients	Isavuconazole volume of distribution in ICU patients in liters. Full pharmacokinetic curves will be taken and an optional sample during the elimination phase of isavuconazole.	Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Isavuconazole proteinbinding in ICU patients.	Isavuconazole proteinbinding in ICU patients described by unbound isavuconazole fraction (fu).	Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Predictability of unbound isavuconazole concentrations	To compare the predicted and observed unbound isavuconazole concentrations in ICU patients: percentage of deviation from predicted.	Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Target attainment of isavuconazole in ICU patients	Percentage of patients reaching the predetermined adequate PK/PD target (isavuconazole trough concentration in mg/l)	At steady state (day 3-7 after start of treatment)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2021
• Primary Completion (ACTUAL): September 29, 2022
• Study Completion (ACTUAL): September 29, 2022

Study Registration Dates

• First Submitted: February 11, 2021
• First Submitted That Met QC Criteria: February 25, 2021
• First Posted (ACTUAL): March 2, 2021

Study Record Updates

• Last Update Posted (ACTUAL): October 26, 2022
• Last Update Submitted That Met QC Criteria: October 23, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: isavuconazole; population pharmacokinetics; protein binding
• Additional Relevant MeSH Terms: Bacterial Infections and Mycoses; Infections; Mycoses; Invasive Fungal Infections
• Other Study ID Numbers: UMCN-AKF-21.02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No