Voriconazole belongs to the class of triazoles with activity against a wide range of yeasts and molds and is first-line therapy for treatment of invasive aspergillosis. The drug is licensed for use in patients 2 years of age and older. In children, voriconazole exhibits near-linear pharmacokinetics as compared with nonlinear pharmacokinetics in adults.1 The increased clearance of voriconazole in patients 2 to 12 years of age has resulted in a recommended intravenous dosage of 7 mg/kg b.i.d. and a fixed oral dose of 200 mg b.i.d. to achieve exposure similar to that in adults receiving 4 mg/kg b.i.d.2
Recently, reports have emerged on the relation between voriconazole exposure and overall success of treatment in adults with suggested provisional cut-off points for voriconazole trough concentrations ranging from 1.0 to 6.0 mg/L.3,4 In a pediatric subpopulation, trough concentrations >1.0 mg/L were associated with a higher likelihood of success and that each voriconazole trough concentration <1.0 mg/L increased the relative risk of death by 6.3-fold.5 Furthermore, it was predicted that 34% of patients between 2 and 12 years of age receiving voriconazole at a dose of 7 mg/kg b.i.d. would not attain the target of >1.0 mg/L.
We performed a retrospective analysis to determine the percentage of adequate trough concentrations in children receiving the current recommended dosing regimen.6
Patients 0 to 18 years of age were identified from our hospital patient records for retrospective analysis if at least one plasma concentration of voriconazole was measured between May 2007 and September 2009. The patients were divided into 2 cohorts: those younger than 12 years and those older than 12 years. Proposed treatment regimen in our center for patients 2 to 12 years of age was either 7 mg/kg b.i.d. intravenously or 200 mg b.i.d. orally. For children >12 years of age, the adult dosage including a loading dose was prescribed. Case report forms were used to collect the following information: age, gender, weight, underlying disease, fungal infection, treatment regimen, outcome, amount of samples taken, timing of sampling relative to dose administration, and dose adjustments. Fungal infections and response to antifungal therapy were retrospectively classified according to the revised definitions of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC-MSG).7,8 Voriconazole trough plasma concentrations were determined at the department of pharmacy of our hospital using a validated high performance liquid chromatography method with fluorescence detection. The assay is externally validated by an international proficiency testing program.9
A trough concentration of <1.0 mg/L was taken as the cutoff point for dose adjustment in patients. For patients with infection at sanctuary sites or disseminated disease (including central nervous system or sinuses), a target concentration of >2 mg/L (based on expert opinion) was pursued because of limited penetration at the target organ.10 Trough concentrations of >6.0 mg/L were considered as an indication for dose reduction.3–5
A Pearson correlation coefficient was calculated to determine whether a correlation existed between administered dose and plasma concentrations. The Pearson χ2 test was performed to determine the correlation between plasma concentrations and the occurrence of side effects.
Patient demographics, underlying disease, and classification and localization of fungal disease are summarized in Table, Supplemental Digital Content 1, http://links.lww.com/INF/A692.
In 5 children <12 years of age, the initial treatment regimen was not in concordance with the recommended dosage as described in the summary of the product characteristics. Two of them were <2 years of age and therefore a therapeutic drug monitoring (TDM)-guided approach with a lower initial dose was chosen. In the age group above 12 years, 3 of 6 were initially not treated according to the guidelines (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A692).
Three patients received combination therapy (cases 6, 7, and 14). Two of them received amphotericin B, the third patient suffered from candidemia and was treated with caspofungin and voriconazole.
Thirty-nine voriconazole plasma concentrations were determined (range, 1–7 per patient). The median time between initiation of voriconazole treatment and the first measurement of plasma concentration was 5 days (interquartile range, 3.0–19.5). Trough concentrations measured in children <12 years of age (n = 25) ranged from <0.1 to 6.0 mg/L (median, 1.25 mg/L), and in children >12 years of age (n = 14) from <0.1 to 9.6 mg/L (median, 1.69 mg/L). Overall, in 8 of 18 patients (44%), the first trough concentration measured after initiation of voriconazole treatment was below the target concentration of either 1 or 2 mg/L. Four of 5 patients (80%) with CNS infection or disseminated infection had initial trough concentrations <2.0 mg/L. In 3 of these 4 patients (75%), the initial trough concentrations was even below 1 mg/L.
From the patients who did not attain the target concentration, 6 of 12 (50%) were 0 to 12 years of age and 2 of 6 (33%) were 12 to 18 years of age.
In 5 of 8 patients, treatment was adjusted after voriconazole concentration measurement, and 3 resulted in target attainment. In the remaining 2 patients, multiple interventions had to be done to eventually achieve the target concentrations (3/5 and 1/2 follow-up samples were considered adequate). In the remaining 3 patients with subtherapeutic concentrations, no dose adjustments were made as the diagnosis of fungal infection had become unlikely (n = 2) or for unknown reason (n = 1).
There was no significant correlation between voriconazole dose and the trough concentration for both children below and above 12 years of age, regardless of the route of administration (P > 0.05 for all 4 groups).
Adverse events were reported in 6 patients (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A692). There was no significant correlation between plasma concentrations and the occurrence of adverse events (P = 0.16). Visual disturbances were not reported. Two patients (cases 7 and 15) had plasma trough concentrations ≥6.0 mg/L, but no clinical signs of toxicity were observed. In 1 patient (case 15), therapy was discontinued 1 week after sample assessment as the diagnosis of fungal infection had become unlikely. In the other patient (case 6), voriconazole was switched to a lipid formulation of amphotericin B because of persistent fever. The correlation between plasma concentrations and outcome was not assessed, because of the small number of patients and due to the use of combination therapy in multiple patients.
We investigated whether the current voriconazole dosing regimen results in adequate exposure in pediatric patients and whether TDM would be beneficial to attain target concentrations between 1 and 6 mg/L. Our study indicates that adequate exposure defined as a trough concentration of >1 mg/L was not achieved initially in 44% of patients. Furthermore, it can be concluded, albeit from a small dataset, that TDM is useful to achieve plasma concentrations within a predefined range of 1 to 6 mg/L.
Although the safety product characteristics provides recommendations for children 2 to 12 years of age, there is no dose recommendation for children below the age of 2 years. In daily practice, however, voriconazole is considered to be the best treatment option for some patients. A TDM-guided approach was chosen in those <2 years of age, with a prudent initial dose when therapy was initiated. None of the 2 children below the age of 2, who started with a dose of 4 mg/kg intravenous b.i.d. and 35 mg orally b.i.d., respectively, achieved the target concentrations. On the basis of this experience, we recommend a higher empiric starting dose together with twice weekly TDM.
Neely et al5 predicted that around 34% of all children receiving voriconazole would not achieve plasma trough concentrations >1 mg/L. In our pediatric patient population, 44% (8/18) had initial trough concentrations below the target concentration of 1 mg/L. The fact that we pursued higher trough concentrations of >2 mg/L, for sanctuary infection sites or disseminated disease, is not the explanation for the higher percentage of children not reaching an adequate trough concentration, because the majority of patients with higher target concentrations had initial trough concentrations below 1 mg/L. Therefore, using a higher target concentration stresses even more the need to perform TDM to assure that these concentrations are reached. TDM is considered a favorable approach to achieve a higher target concentration, due to its direct availability and possibility of timely intervention.
In 3 of 5 patients with follow-up samples, intervention based on the results of TDM resulted in concentrations within the target range upon the first new concentration assessment. Eventually, in all cases where the trough concentration prompted for a dose increase, this resulted in the desired increase in exposure.
We have shown that specifically children aged 2 to 12 years have lower trough concentrations than recommended for therapeutic efficacy and that higher dosages may be needed to obtain exposure within the predefined target range of 1 to 6 mg/L. Furthermore, albeit with limited patients, TDM appears to be a valid tool to guide dosing to achieve concentrations within this target. We recommend performing TDM in pediatric patients on a routine basis to prevent suboptimal exposure when treating life-threatening fungal infections. In our experience, a good general approach in children aged 2 to 12 years would be to assess plasma concentrations once weekly and at a later stage, for example, after 4 weeks of treatment, sampling intervals could be prolonged to once every 2 weeks.
1. Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics
and safety of intravenous voriconazole
after single- or multiple-dose administration. Antimicrob Agents Chemother
2. Karlsson MO, Lutsar I, Milligan PA. Population pharmacokinetic analysis of voriconazole
plasma concentration data from pediatric studies. Antimicrob Agents Chemother
3. Brüggemann RJ, Donnelly JP, Aarnoutse RE, et al. Therapeutic drug monitoring
. Ther Drug Monit
4. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring
in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis
5. Neely M, Rushing T, Kovacs A, et al. Voriconazole pharmacokinetics
and pharmacodynamics in children
. Clin Infect Dis
6. EMA. Vfend: summary of product characteristics, 2009. Available at: http://www.ema.europa.eu/humandocs/Humans/EPAR/vfend/vfend.htm
. Accessed June 2009.
7. de Pauw B, Walsh TJ, Donnelly JP, et al. the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease. Clin Infect Dis
8. Segal BH, Herbrecht R, Stevens DA, et al. Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria. Clin Infect Dis
9. Brüggemann RJ, Touw DJ, Aarnoutse RE, et al. International interlaboratory proficiency testing program for measurement of azole antifungal plasma concentrations. Antimicrob Agents Chemother
10. Lutsar I, Roffey S, Troke P. Voriconazole
concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin Infect Dis