Posaconazole plasma concentrations in critically ill patients.
ABSTRACT 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.
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ABSTRACT: BACKGROUND:Limited information exists regarding the use of posaconazole for treating systemic fungal infections in children, adolescents, and young adults with cancer. At St. Jude Children's Research Hospital, the recommended posaconazole dose in patients weighing less than 34 kg is 18-24 mg/kg daily, given in 4 divided doses. For patients aged 13 years or older or those weighing 34 kg or more, the recommended dose is 800 mg daily, given orally in 4 divided doses.OBJECTIVE:To determine whether the current posaconazole dosing guidelines achieve target posaconazole plasma concentrations of 0.7 μg/mL or greater.METHODS:This retrospective clinical study examined data from patients who received treatment-dose posaconazole and had at least 1 posaconazole plasma concentration measurement.RESULTS:Data from 33 patients who received posaconazole for the treatment of fungal infections were analyzed. The median age of patients was 11.5 years (range 0.5-23.2). Twenty-one of 33 patients (63.6%) had posaconazole concentrations of 0.7 μg/mL or greater (median 1.4; range 0.7-2.98) at the first measurement. The median posaconazole dosage referenced to total body weight in these patients was 20 mg/kg/day. Patients with concentrations less than 0.7 μg/mL (median 0.4; range 0.025-0.69) received lower posaconazole dosages when referenced to body weight (median 12.9 mg/kg/day; p = 0.02). Of the 12 patients with concentrations less than 0.7 μg/mL, 7 (58.3%) were aged 13 years or older.CONCLUSIONS:The current dosing approach for posaconazole yielded therapeutic plasma concentrations more frequently in patients younger than 13 years than in those 13 years or older. This difference may be related to the practice of capping adolescent and young adult doses at the suggested maximum adult daily dose. Therefore, we recommend weight-based dosing in all pediatric, adolescent, and young adult patients with cancer, with routine therapeutic drug monitoring to ensure adequate concentrations.Annals of Pharmacotherapy 06/2013; · 2.57 Impact Factor
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ABSTRACT: Posaconazole is a triazole antifungal agent used as adjuvant or salvage therapy for the treatment of zygomycosis, an invasive fungal infection associated with high mortality. Oral posaconazole absorption is highly variable. We describe the pharmacokinetics of oral posaconazole in a 2-year-old boy with rhino-cerebral-orbital zygomycosis. Seven days after induction therapy for acute lymphoblastic leukemia, he was brought to the emergency department because of left eyelid swelling and was admitted to the hospital. Zygomycosis was diagnosed 12 days later. After we conducted a literature search and consulted with antifungal drug experts, a triple-antifungal regimen consisting of liposomal amphotericin B, caspofungin, and posaconazole was started. Given the severity of the disease, we aimed for posaconazole plasma trough concentrations greater than 1.25 µg/ml; the dosage necessary to achieve this goal was posaconazole 200 mg 4 times/day. After a difficult 105-day stay in the hospital and stabilization of the fungal infection, the patient was discharged. Caspofungin was discontinued at time of discharge, but the patient continued to receive amphotericin B lipid complex 7.5 mg/kg/day intravenously and posaconazole 200 mg orally 4 times/day. This is one of the few case reports describing posaconazole pharmacokinetics in a child younger than 8 years. In patients with extensive zygomycosis, a triple-antifungal regimen, combined with therapeutic drug monitoring of posaconazole, may be helpful.Pharmacotherapy 01/2013; 33(1):e1-8. · 2.31 Impact Factor
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ABSTRACT: There is a male dominance among patients in intensive care units (ICUs). Potentially, this will increase the risk of a skewed male/female distribution in randomised, controlled trials (RCTs). We have evaluated if this has in fact happened when randomising and whether the authors have been aware of that. We performed a systematic search on PubMed from 1 January 2011 to 31 May 2012 using the mesh terms ‘randomized controlled trial’ and ‘intensive care unit’. Twenty-five RCTs with a total of 12,788 patients met the inclusion criteria, with an overall male dominance of 63.6% (P < 0.0001). Eighteen of the 25 papers had an individually statistically significant gender difference in their total trial population. None of the 18 trials with a significant gender difference in their overall trial population had calculated the P-value for this overall difference. In the randomised groups, there was a significant gender difference in five papers. Seventeen had no significant gender difference in the randomised groups, and three papers did not state gender in the randomised groups. This study show that there is a marked male dominance in RCTs conducted in ICUs. We recommend that when planning future RCTs, the authors contemplate if their results can be used indiscriminately among ICU patients if the distribution of males and females is much skewed. It is relevant to determine if ones endpoint can be influenced by gender differences and if there is a risk of gender influence on data, proportional allocation or stratification should be considered.Acta Anaesthesiologica Scandinavica 06/2014; · 2.36 Impact Factor