Intracellular Concentrations of Posaconazole in Different Compartments of Peripheral Blood

Farowski, Fedja; Cornely, Oliver A.; Vehreschild, Jörg J.; Hartmann, Pia; Bauer, Tim; Steinbach, Angela; Rüping, Maria J. G. T.; Müller, Carsten

doi:10.1128/aac.01407-09

Cited by 44 publications

(34 citation statements)

References 14 publications

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“…Similar findings were presented in a case report in which posaconazole accumulation was seen in the lung, liver, spleen, and kidney tissues of a renal transplant patient (8). Our finding was also in accordance with the findings that posaconazole was accumulated in alveolar macrophages and white blood cells in humans (9)(10)(11). A recently published study using an in vitro model of pulmonary epithelial cells found accumulation of posaconazole in cell membranes, especially in the endoplasmic reticulum, which persisted for at least 48 h after the removal of extracellular posaconazole (12,13).…”

supporting

confidence: 81%

Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation

Blennow

Eliasson

Pettersson

et al. 2014

Antimicrob Agents Chemother

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e Few data have been published regarding posaconazole tissue concentrations in humans. We analyzed tissue concentrations in biopsy specimens taken at autopsy from seven patients who received posaconazole prophylaxis because of graft-versus-host disease. The results were compared to plasma concentrations collected before death. Tissue concentrations suggestive of an accumulation of posaconazole were found in the heart, lung, liver, and kidney but not in the brain.

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supporting

confidence: 81%

Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation

Blennow

Eliasson

Pettersson

et al. 2014

Antimicrob Agents Chemother

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“…Farowski and colleagues assessed the intracellular concentrations of posaconazole in peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs), and red blood cells (RBCs) in patients receiving posaconazole for prophylaxis of fungal infections (21). Mean posaconazole concentrations were found to be far higher in PBMCs and PMNs compared to plasma (intracellular-to-extracellular concentration ratios of 22.5 and 7.66, respectively), whereas concentrations in RBCs were approximately 10% of those observed in plasma (21).…”

Section: Is Plasma the Best Sample Matrix For Posaconazole Tdm?mentioning

confidence: 99%

Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring

Dolton

Ray

Marriott

et al. 2012

Antimicrob Agents Chemother

135

126

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“…Several assays for the determination of posaconazole concentration (PC) have been published (5,9,19), but for adequate therapeutic drug monitoring, additional issues have to be clarified. Particularly, the time point for sampling after the administration of the drug remains an open question.…”

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confidence: 99%

Relevance of Timing for Determination of Posaconazole Plasma Concentrations

Heinz

Zirkel

Kuhn

et al. 2011

Antimicrob Agents Chemother

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For posaconazole, drug monitoring is suggested, but the relevance of timing for the determination of posaconazole concentration (PC) remains unclear. We investigated the variation of PC before and 4 and 8 h after the administration of 400 mg of posaconazole. Mean concentrations were 645, 678, and 616 ng/ml. The differences between trough and maximum concentrations were below 20% in 17 and below 30% in 20 of 25 patients. Hence, untimed posaconazole plasma concentrations give reliable information for most patients.Posaconazole was shown to be effective in preventing invasive fungal infections (4, 21). Additionally, the compound is recommended for salvage therapy of invasive fungal infections (1, 15). Low posaconazole plasma concentrations have been associated with a reduced success rate of salvage therapy (22) and an increased risk of clinical failure in the prophylactic indication (8).Remarkable interindividual variation and low or undetectable plasma concentrations in a significant number of patients have been published (6,11,17). Posaconazole has a terminal elimination half-life of 15 to 35 h (6) and is only available for oral administration. Pharmacokinetics may be altered by numerous factors (2, 7, 13), e.g., absorption is impaired by reduced gastric acidity or diarrhea and can be improved by administration together with a fat-containing meal (6,12,18).Several assays for the determination of posaconazole concentration (PC) have been published (5, 9, 19), but for adequate therapeutic drug monitoring, additional issues have to be clarified. Particularly, the time point for sampling after the administration of the drug remains an open question. In clinical practice, the trough level is most often determined in the morning. In the case of suspected toxicity or a breakthrough infection, PC might be of immediate interest, and delaying sampling can become difficult. The purpose of this study is to evaluate first the impact of timing and then the intradaily variability of posaconazole plasma concentration.This study was conducted as an open, single-center trial, in accordance with the local ethical regulations. Patients with hematological malignancies, receiving posaconazole for any indication with a dosage of 400 mg twice a day (BID), were enrolled. Other doses and intervals, particularly 200 mg three times a day (TID), have been excluded, as higher doses and longer intervals are expected to cause a more pronounced variation in daily drug concentration. The aim of the study was to investigate the magnitude of variation in posaconazole drug concentrations at steady state. Therefore, patients were not enrolled before 7 days (mean, 31 days) of posaconazole administration, and patients with severe mucositis, gastrointestinal graft-versus-host disease (GVHD), or diarrhea (more than 3 times daily) were excluded.For pharmacokinetic sampling, blood was drawn in the morning, 12 (11 to 13) h after the last evening dose and before the first daily dose (C trough [C 0h ]), both at the time of maximum expected concentration (4 h ...

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Intracellular Concentrations of Posaconazole in Different Compartments of Peripheral Blood

Cited by 44 publications

References 14 publications

Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation

Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation

Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring

Relevance of Timing for Determination of Posaconazole Plasma Concentrations

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