Posaconazole plasma concentrations in critically ill patients.

Division of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, Australia.
Therapeutic drug monitoring (Impact Factor: 2.43). 06/2011; 33(4):387-92. DOI: 10.1097/FTD.0b013e31821fb197
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    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; · 2.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionPosaconazole is recommended for prophylaxis of fungal infections and for salvage therapy of invasive aspergillosis after stem cell transplantation. An impact of drug concentration on efficacy has been suggested. Methods In this study, we investigated serum levels of posaconazole in 262 samples from 64 allogeneic stem cell recipients. ResultsA high degree of interindividual variation was observed. Concentrations were significantly higher for male patients compared with female patients (median 570 and 426 ng/mL, respectively), but no differences for age or dosing groups (400 mg twice daily [BID] or 200 mg three times a day) could be detected. The predictive value of the first determined posaconazole concentration in steady state and of a concentration >500 and 700 ng/mL at any time was evaluated, compared with patients with a first level Conclusion In patients receiving 400 mg BID, the mean rate of serum levels >500 ng/mL in subsequent determinations was higher, if the first serum concentration during steady state was >300 ng/mL (mean 61.1%, median 60%, P = 0.002) or >500 ng/mL (67.7%, median 75%, P = 0.002). Based on this retrospective analysis, a posaconazole serum concentration >500 ng/mL at any time point might also help to predict sufficient drug concentrations.
    Transplant Infectious Disease 10/2013; · 1.98 Impact Factor
  • [Show abstract] [Hide abstract]
    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