DISCUSSION
In the present study, transaminase values increased 2- to 3-fold during PP use, and five patients (8.9%) presented breakthrough fungal infections.
Oral posaconazole is an alternative ’off-label’ medication for patients under 13 years of age. However, there are concerns related to the bioavailability of the drug, which may be variable, making it difficult to achieve optimal plasma levels of posaconazole in pediatric patients, even with an adequate dose regimen (9). Our patients received dosing schemes similar to those reported in previous studies (12 mg/kg/day) (10.11), with the variations observed in our institution being due to a non-standardized prescription regimen during the study period. On the other hand, a previous study demonstrated that doses less than 12 mg/kg/day could be related to suboptimal posaconazole plasma levels (values ​​less than 0.7 μg/mL) (12). In contrast, another study, which administered oral posaconazole to pediatric patients, found that only 31% of patients aged 2 to 6 years achieved optimal average steady-state posaconazole concentrations (calculated as the area under the curve (AUC)/dose interval in 24 hours) between 500 and 2500 ng/mL, using doses of 12 mg/Kg/day, with a dosing interval of 2 times per day (7).
In this regard, some authors suggest an increase in the frequency of the dose interval to achieve optimal plasma levels due to the saturable bioavailability of posaconazole (13). An initial dose of PP of 200 mg 3 times a day (oral suspension) is recommended in pediatric populations between 6 months to 6 years of age, while in children between 7 and 12 years, 300 mg 3 times a day is recommended in the case of oral suspension (for children who can not take pills), or 200 mg three times a day, in the case of pills, increasing the dose if the therapeutic drug monitoring (TDM) is less than 0.7mg / L (13).
Other factors can affect the absorption of posaconazole, such as the concomitant use of proton pump inhibitors and the presence of mucositis, which limit the achievement of optimal prophylactic and therapeutic levels (14,15). One study reported that the use of proton pump inhibitors was associated with a 42% reduction in posaconazole bioavailability in children younger than 13 years (13). In our study, 33.9% used proton pump inhibitors and 7.1% developed mucositis during PP use. The bioavailability of posaconazole was not analyzed in this study, therefore it is not possible to evaluate the effect of the use of proton pump inhibitors and the presence of mucositis on this variable.
Concerning possible adverse events due to the use of posaconazole, several studies have described clinical findings similar to ours, corresponding mainly to gastrointestinal manifestations such as abdominal pain and nausea (10,11,16). On the other hand, the 2- to 3-fold increase in ALT and AST values observed in our study has also been described in other studies carried out in populations of children who received posaconazole (16,17). In addition, comparative studies of posaconazole and other azoles employed for antifungal prophylaxis in pediatric patients described the development of adverse events such as hepatotoxicity (10), reporting a significant increase in ALT and AST values from the serum value at the beginning and the maximum values during the use of different groups of azoles, including posaconazole (11).
In contrast, other studies observed only one case of breakthrough fungal infection by Aspergillus fumigatus (3.0%), in patients under 18 years of age during PP use (17), with other series in children reporting no case of breakthrough fungal infection during PP (6,16). In a study comparing itraconazole, voriconazole, and posaconazole used as oral antifungal prophylaxis in pediatric patients undergoing HSCT, no case of breakthrough fungal infection was found in the posaconazole group, while in the itraconazole and voriconazole groups there were 4% and 6% of possible cases of IFI, respectively (11). We found a higher number of breakthrough fungal infection cases (5 cases; 8.9%) compared to the previously described reports. It should be noted that three of these cases concomitantly used proton pump inhibitors, two did not receive the drug along with high-fat meals, and one had mucositis. This is important,since it has previously been described that these variables can decrease the bioavailability of the drug and thereby favor the development of breakthrough fungal infection (15).
In patients younger than 13 years, the main prophylactic antifungal agents (with activity against filamentous fungi) recommended are itraconazole and voriconazole with the use of TDM, in both cases (3,18). Posaconazole is an ’ off-label ’ alternative in this group of patients, and it also requires TDM to ensure adherence and adequate exposure to the drug, especially when used in oral suspension and in children under 13 years of age (19). However, liver toxicity and breakthrough fungal infection episodes developed in some patients during the use of posaconazole in our study. To date, in Peru, no public health center performs TDM for antifungals, and in most health centers the oral suspension presentation of voriconazole is not available as a recommended prophylactic alternative in children older than 2 years (18).
The clinical and laboratory findings in our study may not only be due to the use of posaconazole, but also to the use of another medication or interaction with other drugs used in this group of patients. Furthermore, TDM of posaconazole was not performed and therefore a relationship between the adverse events observed (clinical, laboratory, and breakthrough fungal infection) and the plasma levels of the drug (supra-therapeutic or infra-therapeutic) could not be determined.
In conclusion, patients less than 13 years of age receiving PP showed an increase in transaminase values, and the development of breakthrough fungal infections, demonstrating the need for TDM during this type of prophylactic treatment.