Single Dose Population Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients

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.