Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04777058 |
| Other study ID # |
UMCN-AKF-21.02 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2021 |
| Est. completion date |
September 29, 2022 |
Study information
| Verified date |
October 2022 |
| Source |
Radboud University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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).
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.
