Pharmacokinetics of anidulafungin (Ecalta ®) given intravenously as antifungal prophylaxis to recipients of an allogeneic haematopoietic stem cell transplant following myeloablative chemotherapy or patients receiving intensive chemotherapy for AML-MDS who are at high risk for developing invasive fungal disease

Alternate dosing strategies of echinocandin drugs might provide a better
efficacy in the treatment of fungal infections as compared to the current label
dosing strategy. Before conducting a controlled efficacy trial of
echinocandines in haematology patients, the pharmacokinetics of these alternate
dosing strategies need to be tested before bringing this idea to practice in a
large randomised trial.
Therefore we want to conduct a pharmacokinetic study with anidulafungin given
every 48 hours or every 72 hours. This research can be performed best in a
group of patients at high risk for de-veloping invasive fungal infections.
Recipients of an allogeneic haematopoietic stem cell transplant (HSCT) or
patients receiving intensive chemotherapyfor acute myeloid leukaemia (AML) or
myelodysplastic syndrome (MDS) are at a relatively high risk of developing
invasive fungal infections and are therefore candidates for primary
prophylaxis. However, the options are limited to fluconazole which affords no
protection against mould infections. Amphotericin B is not considered useful
because of its desoxycholate formulation has too many side effects and its
lipid formulations are too expensive nor have the broad-spectrum triazoles
itraconazole and voriconazole proved their value in this setting. Anidulafungin
belongs to the class of echinocandins, attacking specifically the ß 1-3 -
D-glucan synthase of the cell wall. It has relatively few side effects and
appears safe and effective for treating Aspergillus and Candida infections.
Since these two genera account for 90% of fungal infections in HSCT recipients
the drug would seem an ideal candidate for prophylaxis.

Importantly, nothing is known about the pharmacokinetics of alternate dosing
regimens of anidulafungin in this patient population. Therefore a
pharmacokinetic study of a homogenous cohort of patients is necessary to test
the assumption, that adequate exposure is obtained with alternate dosing and
that it is safe.

The primary objective of this trial is as follows:
• To determine the pharmacokinetics of anidulafungin given once in every 2 days
(q48h) or once in every 3 days (q72h) to patients undergoing an allogeneic
haematopoietic stem cell transplant following myeloablative chemotherapy or
receiving intensive chemotherapy for AML-MDS

The secondary objectives of this trial are as follows:
• To determine whether adequate exposure is attained by patients undergoing an
allogeneic haematopoietic stem cell transplant following myeloablative
chemotherapy or receiving in-tensive chemotherapy for AML-MDS when using a q48
hour or a q72 hour dosing regimen
• To determine whether infusion time can be advanced to 2 mg/min (both
regimens)
• To determine the safety of anidulafungin in this patient population*

This is an open-label, single-period, single-centre, phase-II, multiple-dose
trial in 20 patients receiving an allogeneic haematopoietic stem cell
transplant following myeloablative chemother-apy or receiving intensive
chemotherapy. After meeting the inclusion criteria and passing the exclusion
criteria, the 20 subjects will be divided into 2 groups of 10 subjects.

During this study, patients will receive, depending on the group, 5 or 8
infusions of study medication.
20 participants will be divided into two groups of 10 patients each. After 5 or
8 infusions of study drugs, there will be a follow-up period of 9 days.

First and most important of all, there is a benefit for the patient who will
receive antifungal prophylaxis, like recommended in the ECIL guidelines as
recently published by Maertens et al.

Anidulafungin, like other echinocandins, is well tolerated with less side
effects than fluconazole.
Administration is limited to either 5 or 8 administrations of anidulafungin,
depending on the treatment group.
All patients will be managed with a central venous catheter. This will be
according to regular practice in the very near future and is thus regarded as
no additional burden.

For specific, drug related, side effects, we refer to the study protocol.