Systemic Fungal Infections Clinical Trial
Official title:
Single Dose Population Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients
The purpose of this study is to try to find out how critically ill patients receiving the
anti fungal medication, posaconazole, process it in their body. Investigators would like to
study if the recommended doses of posaconazole achieve adequate concentrations in the
patients blood to treat fungal infections.The disease process in critically ill patients can
profoundly influence the concentration of anti fungal medication in the blood. The process by
which a drug travels through the body in blood, how it is broken down and removed by the body
is called pharmacokinetics (PK).
This information is important to know because if antifungal levels are low in the blood, the
fungal infection has an opportunity to become resistant to the antifungal medication which
can lead to the medication being less effective against the fungal infection potentially
exposing future patients with infection to a limited range of effective antifungals.
Investigators can measure the PK by taking blood samples at specific times after the anti
fungal medication is given.
This study will enroll 8 patients who are admitted to the intensive care unit and are being
treated with an antifungal medication for a fungal infection. Patients will be consented and
given a single dose of posaconazole and serial blood samples will be collected just prior to
the dose and at 15, 45,75 minutes during the infusion and at 3, 5, 8, 12, 18, 24, 30 36 and
48 hours . Information about the patients stay in the ICU will also be collected including
blood pressure, temperature, blood test results.
Posaconazole is a new extended spectrum triazole active against a range of yeasts and molds
including Aspergillus, Candida, Coccidioides, Cryptococcus neoformans, Fusarium, and
Zygomycetes. It may be used for the prevention of invasive fungal infections in
immunocompromised patients including febrile neutropenic patients and those receiving
immunosuppressant drugs for graft-vs-host disease during stem cell transplantation. It may
also be used for treatment of systemic fungal infections.The use of posaconazole in ICU
patients has been limited to stable patients to ensure reliable bioavailability from the oral
formulations. Oral formulations have important limitation in that they cannot be used in
critically ill patients who may be unable to take oral doses or bioavailability may be
compromised due to erratic absorption. Recently, an intravenous (IV) formulation has been
developed to address these limitations. Initial pharmacokinetic (PK) investigations of the IV
formulation were conducted in hematology patients, with further data in other patient
populations still forthcoming; particularly in the critically ill where the IV formulation
would probably be used most frequently.
Most of the available PK data for posaconazole is from non-critically ill patients who
received the oral formulation. Although the absorption phase of the kinetics is not relevant
for the IV formulation, data on the distribution, metabolism and elimination properties would
still be informative of the IV kinetics. The tissue distribution of posaconazole is extensive
with a very large volume of distribution owing to its high lipophilicity. It is highly bound
to plasma proteins (98-99%) and therefore very likely to be affected by the variable changes
in plasma protein concentration in critically ill patients. The major elimination pathway of
posaconazoleis through biliary excretion (about 77%) of mainly the unchanged parent compound
and the rest through renal execration of as a glucuronide conjugate.
A number of studies have described PK variability of posaconazole due to altered
absorption/bioavailability which can frequently result in sub-therapeutic plasma
concentrations, forming strong case for therapeutic drug monitoring. Nonetheless, it is
unclear whether the observed low concentrations can also be explained, at least in part, by
other factors such as disease-related PK changes or if the obvious plausibility of altered
absorption has masked such investigations. Most population PK models described so far are
based on one compartment models, which do not reveal if the observed variability in
concentrations is due to changes in PK parameters such as volume of distribution or
clearances. The influence of disease state on these PK parameters has been extensively
described for several antimicrobials in the critically ill patient populations. Although data
on the new IV formulation of posaconazole in this patient population is lacking, there is
evidence from previous PK studies on the oral formulation that PK variability not observed in
healthy study participants was observed in patients with invasive fungal infections, although
it was explained primarily in relation to altered bioavailability from the oral formulation.
In surgical ICU patients low plasma concentration of posaconazole were observed, after
administration via nasogastric tube. Similar findings were reported in general ICU patients.
Although the explanation in these reports was again the irregular absorption, the influence
of other pathologic changes remains to be investigated. A PK evaluation of IV posaconazole in
critically ill patients, not confounded by the absorption factor, would reveal if there is
any pathophysiology-induced PK alteration. Such a study will also give insight into the
dose-exposure relationships and optimal treatment regimen.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
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