Relevance of Timing for Determination of Posaconazole Plasma Concentrations

Abstract

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 ...

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

“…In a comparison of two patients receiving FDA-approved dosing and exhibiting steady-state trough levels of 700 ng/ml, one receiving the tablet and one receiving the suspension, the AUC will be greater for the patient receiving the tablet formulation. At any given trough level, the AUC will always be greater if once-daily PCZ tablets are used to reach the target as compared to the fractionated and frequent dosing of the PCZ suspension (19). Therefore, standard dosing with the tablet formulation, even when yielding low trough values, may achieve AUC values similar to those seen for patients with trough levels in excess of 700 ng/ml with the suspension formulation.…”

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

“…While this may justify the use of "untimed" concentrations, until recently this assumption had not been investigated. In a cohort of patients with hematological malignancies receiving posaconazole at 400 mg twice daily, Heinz et al compared mean posaconazole concentrations timed at a trough, 4 h postdose, and 8 h postdose (29). Mean concentrations were found to be 645, 678, and 616 ng/ml, respectively, with the majority of patient trough and 4-h posaconazole concentrations differing by Ͻ20% (29).…”

“…In a cohort of patients with hematological malignancies receiving posaconazole at 400 mg twice daily, Heinz et al compared mean posaconazole concentrations timed at a trough, 4 h postdose, and 8 h postdose (29). Mean concentrations were found to be 645, 678, and 616 ng/ml, respectively, with the majority of patient trough and 4-h posaconazole concentrations differing by Ͻ20% (29). Although the use of trough posaconazole concentrations is preferable to ensure that adequate exposure is maintained, those findings indicate that concentrations measured earlier in the dosing interval may still be useful for posaconazole TDM.…”

Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration

“…Posaconazole dosing records for each patient were used to verify the time of posaconazole concentration sampling in relation to dose. As posaconazole is known to exhibit a reasonably flat concentration-time profile at steady state, with similar concentrations measured at 4, 8, and 12 h after dose (14), all posaconazole concentrations irrespective of sampling time after dose were included in the analysis. Posaconazole concentrations were excluded from the analysis if measured within the first 7 days of dosing with posaconazole or if the patient's dosing record indicated missed posaconazole dosing prior to sampling for quantitation of posaconazole.…”