No drugs were licensed in Germany for use as antifungal prophylaxis in children after BMT at the time when this retrospective survey took place. Furthermore, we had observed breakthrough infections with the treatment of azoles other than posaconazole in the past. In a historical group of 50 pediatric patients whom we had treated in our center with an antifungal prophylaxis with itraconazole after allogeneic HSCT, three possible fungal infections were observed. This data is in concordance with data obtained at other centers . These reasons prompted our choice of posaconazole, due to its promising results in adult patients. To address specific questions with regard to pharmacokinetic evaluations, we conducted plasma level measurements. According to the current guidelines for antifungal management in adult patients, posaconazole is recommended as primary antifungal prophylaxis following allogeneic HSCT . Based on the data on posaconazole as oral antifungal prophylaxis in adults we decided to use posaconazole in pediatric patients as well [12, 13].
We retrospectively assessed data on the plasma levels, efficacy, safety, and tolerability of posaconazole in 60 pediatric patients under 12 years of age after HSCT. Varying dosages of posaconazole as antifungal prophylaxis and therapy for invasive fungal infections have been reported in adults [5, 12], while dosages for pediatric patients have not yet been defined [20, 21]. We adapted the recommended prophylactic dosage of 600 mg/day in adults to the weight of pediatric patients . Initially, the frequency of administration of posaconazole was 5 mg/kg b.i.d. However, data became available showing that trough levels of pediatric patients were lower and less stable compared with those reported in adults [12, 13, 22, 23]. Therefore, the frequency of administration and daily dosage were increased to 4 mg/kg t.i.d.
Posaconazole trough levels under the latter regimen were consistently higher than trough levels in patients who received posaconazole b.i.d. and only slightly lower than posaconazole trough levels in adults undergoing posaconazole prophylaxis [12, 13]. In another report posaconazole levels > 0.5 mg/L correlated with a better outcome . Although we mostly found lower values in our patient cohort, no invasive fungal infections were observed. This illustrates that a prospective randomized controlled study in pediatric patients is of pressing importance to verify this data. There is only one published pediatric study on dose determination involving a small group of 12 pediatric and juvenile patients (median age, 15 years) with invasive fungal infections; the therapeutic dose of posaconazole in 11 of 12 patients was 800 mg/day in divided doses with a median posaconazole through level of 579 ng/mL (range, 85.3 - 2891 ng/mL; mean, 776 ng/mL) . In our prophylaxis study, we observed lower posaconazole trough levels (median, 404 ng/mL; range, 291 - 1243 ng/mL; mean, 476 ± 246.84 ng/mL) from day 7 after the start of treatment at 4 mg/kg t.i.d. A randomized crossover study with healthy subjects showed the highest posaconazole levels during and after a high-fat meal and with avoidance of proton pump inhibitors . Most of the pediatric patients enrolled in our retrospective analysis received a proton pump inhibitor (76.67%, n = 46) or a H2 receptor antagonist (10%, n = 6) at least once a day during analysis of posaconazole trough levels; it is probable that the trough levels would be higher with avoidance of proton pump inhibitors.
Only a few studies have been published on the usage of posaconazole in pediatric patients with a small number of cases. A multi-center retrospective survey reported data on 15 pediatric patients (median age, 10 years) with invasive fungal infections, most of them with hemato-oncological malignancies, who received posaconazole salvage therapy at a median dosage of 21 mg/kg body weight (range, 4.8 - 33.3 mg/kg). Posaconazole was effective as salvage therapy for proven and probable invasive fungal infections . Another retrospective survey on the off-label use of posaconazole as secondary prophylaxis and rescue therapy included 15 pediatric patients (median age, 10 years). Twelve of these patients experienced an invasive fungal infection, i.e. proven aspergillosis in one patient, probable aspergillosis in ten patients and possible mycosis in one patient. Three patients received posaconazole as primary (n = 2), and secondary (n = 1) prophylaxis in high-risk situations, i. e. treatment with steroids, acute GvHD, and haploidentical HSCT. 9 of the 15 patients were post-HSCT. Patients received varying dosages, including 200 mg/day (t.i.d.) in 12 cases, 400 mg/day (b.i.d.) in two cases, and 100 mg/day (t.i.d.) in a single patient . Posaconazole was well tolerated and showed significant clinico-radiological improvements in 9 of these 12 patients. In our pediatric patients, we observed a significant but moderate and reversible increase in the liver parameters ALT and AST. This finding corresponds with observations made in a retrospective study of salvage therapy in pediatric patients . The survey also reported side effects similar to those in our analysis, such as nausea and vomiting. Drug interactions involving posaconazole and calcineurin inhibitors can occur due to inhibition of the CYP3A4 isoenzyme . We observed a significant increase in the CsA plasma concentration in 16 (57.1%) of the 28 pediatric patients in our cohort. An average CsA dose reduction of 22% (range, 10 - 32%) was sufficient to adjust for this reaction. Similar elevated CsA trough levels were also observed in up to 41% of patients in another retrospective review of adult and pediatric HSCT recipients after voriconazole administration . The limitations of the measured posaconazole levels in our analysis are that they took place retrospectively from excess material remaining after laboratory analyses which had been routinely cryopreserved, and that only on arbitrary time points after day seven (the point commonly known to be the time when a steady state of posaconazole levels plasma is reached) were possible. It is of utmost importance to establish a pharmacokinetic analysis within the framework of a prospective, randomized study in pediatric patients.