Pharmacokinetic Analysis during Antifungal Prophylaxis with Posaconazole Suspension in Pediatric and Adolescent Patients after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Döring Michaela , Cabanillas Stanchi Karin Melanie , Queudeville Manon , Feucht Judith , Schlegel Patrick , Feuchtinger Tobias , Lang Peter , Handgretinger Rupert , Heinz Werner J. 
Published: October 2019

Abstract
Background: Invasive Aspergillosis and Candidiasis are some of the major infectious complications after allogeneic hematopoietic stem cell transplantation (HSCT) with an incidence between 10 - 30% and an associated mortality rate between 50 - 90%. Posaconazole is an extended spectrum triazole with clinical activity against Aspergillus spp., Candida spp., Zygomycetes, Fusarium spp. and other rare causes of invasive fungal infections such as Cryptococcus neoformans and Histoplasma capulatum. Due to the excellent results regarding efficacy, safety and feasibility that were shown in prospective studies in adults, we have been using posaconazole for antifungal prophylaxis in pediatric patients for several years now. Bioavailability of posaconazole suspension is impaired by low gastrointestinal resorption due to its lipophilicity. Investigations on adult patients after HSCT have shown that posaconazole resorption depends strongly on the gastric conditions, e.g. intestinal graft-versus-host disease, fat uptake during drug administration, or concomitant medication such as proton pump inhibitors, However, there is insufficient data on the pharmacokinetics of posaconazole in pediatric patients. This single-center analysis evaluated the pharmacokinetic properties as well as efficacy, safety, and feasibility of posaconazole during the initial four weeks of oral antifungal prophylaxis in pediatric and adolescent patients after allogeneic HSCT.
Methods: 31 patients with hemato-oncological malignancies with a median age of 6 years (range 6 months - 17.6 years) received posaconazole as antifungal prophylaxis after allogeneic HSCT during the post-transplant period. The posaconazole trough levels were measured for all patients included in this analysis on day 2, 3, 5, 7, 10, day 14±1, and day 28±3 after the first intake of posaconazole suspension. The median observation period was 109 days (range 39 - 206 days), and the median treatment period was 97 days (range 25 - 192 days).
Results: No proven, probable or possible fungal infection according to the EORTC/MSG guidelines was observed in the analyzed patient group. A total of 158 posaconazole trough levels were evaluated. During the first five days after start with posaconazole oral prophylaxis, the posaconazole trough level increased continuously. Median posaconazole levels registered 70.5 ng/mL (mean 78.89±50.19 ng/mL) on day 2, 133 ng/mL (mean 156.2±80.5 ng/mL) on day 3, and 209 ng/ml (mean 259.2±184.2 ng/mL) on day 5. Four weeks after start with oral posaconazole prophylaxis, the posaconazole level was at median 633.5 ng/mL (mean 731.7±407.8 ng/mL; range 290 - 1664 ng/mL). These values were significantly higher in comparison to the posaconazole levels on day 10 (P=0.016) with median 324 ng/mL (mean 446.7±350.8 ng/mL; range 104- 1581 ng/mL), and on day 7 (P=0.007) with median 252 ng/mL (mean 390.1±459.7 ng/mL; range 54 - 2441 ng/mL). On day 14 after start of antifungal prophylaxis the posaconazole plasma concentrations reached a stable level with a median of 529 ng/mL (mean 643.3±493.3 ng/mL; range 115 - 2081 ng/mL), and revealed no significant difference (P=0.24) in comparison to values analyzed four weeks after the start with posaconazole. The rates of potentially clinical drug related adverse events were very low. There was a significant transient increase (P<0.001) of transaminases ALT and AST during prophylaxis.
Conclusions: Posaconazole suspension is effective in preventing invasive fungal infections in pediatric patients. 58% of the samples showed a sufficient posaconazole concentration above 500 ng/mL on day 14. 72% showed a sufficient posaconazole concentration four weeks after start with posaconazole prophylaxis.

Disclosures
No relevant conflicts of interest to declare.