Posaconazole Plasma Concentrations in Critically Ill Patients
Division of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, Australia. Therapeutic drug monitoring
(Impact Factor: 2.38).
06/2011; 33(4):387-92. DOI: 10.1097/FTD.0b013e31821fb197
Posaconazole is an azole antifungal agent with a broad spectrum of activity and a manageable side-effect profile. Although the pharmacokinetics of posaconazole have been described in healthy volunteers who received the drug by means of a nasogastric tube or with nutritional supplements, the pharmacokinetics of posaconazole have not been reported in critically ill patients.
Twenty-seven patients in the general intensive care unit managed according to standard protocols were randomly allocated to dose regimens of either 400 mg twice daily or 200 mg 4 times daily. Plasma samples were collected for pharmacokinetic analysis after the first dose and at steady-state. Posaconazole plasma concentrations were compared with suggested effect targets for prophylaxis and treatment.
Mean Cmin steady-state plasma concentrations of posaconazole were low for both regimens (306 and 137 ng/mL for 400 mg twice daily and 200 mg 4 times daily regimens, respectively), as was total exposure to posaconazole in each group [area under the concentration-time curve (AUC0-t) for first dose: 761 and 299 μg·h/L]. Only 17% of patients achieved steady-state Cmin posaconazole plasma concentrations above the suggested target for prophylaxis, and only one patient had a Cmin posaconazole concentration that exceeded the suggested target for treatment effect. Systemic exposure to posaconazole seemed to be subtherapeutic in most patients in this cohort. Poor absorption of posaconazole due to drug interactions may explain the low systemic exposure; however, further investigation is necessary.
These data suggest that there is a need for an intraveneous formulation of the drug if it is to be used effectively in critically ill patients, and therapeutic drug monitoring is an essential tool in this setting to identify patients with low systemic exposure to prevent therapeutic failure.
Available from: ncbi.nlm.nih.gov
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ABSTRACT: Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.
Available from: Torsten Hoppe-Tichy
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ABSTRACT: Abdominal surgery may affect intestinal absorption and the resulting levels of posaconazole in the blood. We measured plasma
posaconazole levels in surgical intensive care unit (SICU) patients and tried to develop a predictive population pharmacokinetics
model. A total of 270 samples from 15 patients receiving posaconazole via nasogastric tube were measured by high-performance
liquid chromatography (HPLC). SICU patients showed lower plasma drug concentrations, a higher apparent clearance, and a higher
volume of distribution than those in hematology patients, possibly due to poor absorption.
Available from: Sharon Chen
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ABSTRACT: Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H(2) antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.
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