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Micafungin

Clotrimazole

Miconazole

Antifungal Agents

treatment for 8 days with intravenous micafungin twice weekly

alternate dosing

daily dosing

micafungin

Roger Brüggemann

The primary objective of this trial is as follows:

To determine the pharmacokinetics of micafungin given twice weekly in patients at risk for developing an invasive fungal disease (patients who are being treated for acute or chronic graft versus host disease; patients receiving reduced intensity conditioning for Stem Cell Transplant (SCT); receiving first remission induction chemotherapy for Acute Myeloid Leucaemia (AML)/MyeloDysplasticSyndrome (MDS)) compared to the pharmacokinetics of micafungin given daily.

The secondary objective of this trial is as follows:

To determine whether adequate exposure of micafungin is attained. To determine the safety of micafungin in this patient population

Micafungin has been shown to be a reasonable option for treating invasive aspergillosis in hematopoietic stem cell transplantation (HSCT) recipients and has proven as effective as fluconazole for prophylaxis. Whilst micafungin has much to offer, little is known about its pharmacokinetic profile in specific patient populations, specifically concerning alternate dosing strategies with increased dosages over a prolonged dosing interval. Sufficient data are lacking up to now for twice weekly administration of micafungin as antifungal prophylaxis. Decreasing the dosing frequency to twice weekly seems a reasonable approach considering the long terminal elimination life (i.e. 10-17 h) and considering the data available from murine models that support the use of less frequent dosing with higher dosages.

It will enable us to characterize both the pharmacokinetics of micafungin in the hematology cohort and directly compare the exposure to the alternate dosing strategy.

Pharmacokinetics of Micafungin Given Twice Weekly Intravenously Compared to Micafungin Given Daily to Patients at Risk for Developing an Invasive Fungal Disease

Pharmacokinetics of Micafungin (Mycamin ®) as Antifungal Prophylaxis Given Twice Weekly Intravenously Compared to Micafungin Given Daily to Patients at Risk for Developing an Invasive Fungal Disease.

Full pharmacokinetic curves will be taken op Day 4 or 5 and Day 8 (micafungin). AUC of two dosing regimens will be compared.

to perform Monte Carlo simulations to provide the scientific background for alternate dosing strategies in the prophylactic setting

number and severity of adverse events will be recorded during the study and both treatment regimens will be compared

Radboud University Medical Center

Posaconazole

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

* Start with posaconazole IV 300mg BID on the first day. Posaconazole will be infused over a period of 90 minutes.
* Days 2-7 patients will receive posaconazole IV 300mg QD.
* Days 8-12 patients will receive posaconazole PO 300mg QD.
* Days 13-16 patients will receive posaconazole PO 200mg QD.
* 3 PK curves will be determined on days 7, 12 and 16 (after the 7th, 12th and 16th dosage).

* Start with posaconazole PO 300mg BID on the first day.
* Days 2-7: patients will receive posaconazole PO 300mg QD.
* Days 8-12: patients will receive posaconazole IV 300mg QD. Posaconazole will be infused over a period of 90 minutes.
* Days 13-16 patients will receive posaconazole IV 200mg QD.
* 3 PK curves will be determined on days 7, 12 and 16 (after the 7th, 12th and 16th dosage).

posaconazole

Roger Brüggemann, PhD, PharmD

This study evaluates the the pharmacokinetics of posaconazole (new solid oral and IV) given as prophylaxis to patients who are at risk for developing fungal infections after receiving conditioning therapy (except strictly non-myeloablative (NMA)) for allogeneic Stem Cell Transplant (SCT), remission induction chemotherapy for acute myeloid leukemia (AML) or myelo dysplastic syndrome (MDS) or being treated for severe graft versus host disease (GvHD) and determines the impact of mucositis on the pharmacokinetics of posaconazole new solid oral.

In 2014, the new intravenous and solid oral formulation of posaconazole were marketed. This offers new treatment possibilities, specifically in patients previously unable to attain adequate exposure to posaconazole solution. To the opinion of the researchers, only limited data are available on the pharmacokinetics (PK) of the new formulations of posaconazole, however, these use strictly selected patients or healthy volunteers, but more importantly, specific aspects related to the PK remain unsolved. Despite the fact that adequate exposure is attained using the new solid oral formulation, it is hypothesized that oral bioavailability of posaconazole may be impacted during mucositis. Whether mucosal barrier injury impacts the absorption of posaconazole or alters presystemic clearance is still unknown. Therefore, it seems prudent to conduct a trial in a group of patients that will experience a severe degree of mucositis to identify changes in absorption of posaconazole and resolving the impact of various stages of mucositis on the PK of posaconazole by linking PK of posaconazole to markers of mucositis (citrulline). This research may also serve as a model for other drugs and allows for direct translations in improving patient care. For this purpose it is needed to determine the PK using both IV and PO dosing of posaconazole.

Pharmacokinetics of Posaconazole (Noxafil®) as Prophylaxis for Invasive Fungal Infections

Plasma samples drawn on t=0 (pre-dose), 0.5, 1 (just prior to end of infusion), 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post infusion or post intake will be taken op day 7, day 12 and day 16 to determine posaconazole concentrations. Area Under the Curve of two routes of administration and two dosing regimens will be determined.

Full pharmacokinetic curve (plasma samples drawn on t=0 (pre-dose), 0.5, 1 (just prior to end of infusion), 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post infusion or post intake) will be taken op day 7, day 12 and day 16 (posaconazole). Impact of mucositis on oral absorption will be determined by comparing AUCs after intravenous administration with oral (tablet) administration in patients with mucositis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pharmacokinetics of Micafungin Given Twice Weekly Intravenously Compared to Micafungin Given Daily to Patients at Risk for Developing an Invasive Fungal Disease	NCT02172768	Acute Graft Ver... Allogeneic Stem... Acute Myeloid L... Myelo Dysplasti...	alternate dosin... daily dosing micafungin	18 Years -	Radboud University Medical Center
Pharmacokinetics of Micafungin Given Twice Weekly Intravenously Compared to Micafungin Given Daily to Patients at Risk for Developing an Invasive Fungal Disease	NCT02172768	Acute Graft Ver... Allogeneic Stem... Acute Myeloid L... Myelo Dysplasti...	alternate dosin... daily dosing micafungin	18 Years -	Radboud University Medical Center
Pharmacokinetics of Posaconazole (Noxafil®) as Prophylaxis for Invasive Fungal Infections	NCT02805946	Allogeneic Stem... Acute Graft Ver... Acute Myeloid L... Myelo Dysplasti...	posaconazole	18 Years -	Radboud University Medical Center

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