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.