Abstract
OBJECTIVE
Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations.
METHODS
This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason.
RESULTS
There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early.
CONCLUSIONS
The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.
Keywords: antifungal, invasive fungal infection, pediatrics, pharmacist, posaconazole, young adults
Introduction
Posaconazole is a broad-spectrum triazole antifungal agent with activity against invasive yeasts and molds, including Candida and Aspergillus species.1 This agent is indicated for prophylaxis and treatment of invasive fungal infections (IFIs) in immunocompromised and neutropenic individuals who are at high risk for developing IFIs, including those receiving chemotherapy for acute myeloid leukemia and hematopoietic stem cell transplantation.2–4 Posaconazole is currently available in multiple formulations that are FDA approved for differing age ranges, including a delayed-release (DR) tablet and oral suspension for patients 13 years and older, and IV solution for 18 years and older.4 The limited clinical data available in the pediatric population have contributed to poor understanding regarding the appropriate dosing strategies and target plasma concentration of posaconazole in this population. Moreover, the complexity of pharmacokinetics and pharmacodynamics within the pediatric population adds uncertainty to the use of posaconazole in prophylaxis and treatment against IFIs.5–9 Despite the increased use of posaconazole off-label in younger patients during the last decade,10 clinical data elucidating the optimal dosing and appropriate therapeutic drug monitoring target plasma concentration of posaconazole within the pediatric population remain scarce.
The lack of data supporting posaconazole target plasma concentrations for the pediatric population has led many institutions to use trough serum concentration goals based on adult data of ≥700 ng/mL for prophylaxis and ≥1000 ng/mL for treatment of IFIs.11 While applying these goals to the pediatric patient population, some studies have used an initial fixed-dose approach based on the patient's age, whereas others have used a weight-based dosing approach to achieve the target trough concentration goals.12,13 Variability in the posaconazole dosing regimen technique5,7,8,12–14 suggests a need to bridge the gap between the optimal dose and target plasma concentration of posaconazole for prophylaxis and treatment of IFIs in the pediatric population.
The objective of this study is to contribute to the currently lacking data regarding optimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent plasma concentrations. Additionally, this study aims to contribute to data regarding patients who develop breakthrough IFIs while on posaconazole for prophylaxis.
Methods
Inclusion and Exclusion Criteria. This retrospective, observational study was conducted at the North Carolina Children's Hospital after approval from the Institutional Review Board. Data collected for this study included patients admitted between April 2014 and March 2019. Patients aged 1 to 21 years who were prescribed posaconazole (oral suspension, DR tablet, or IV solution) and had a steady-state plasma concentration drawn during an inpatient hospital stay were included in this study. A steady-state concentration was defined as being drawn appropriately during the 5 to 7 days after initiation of posaconazole DR tablets or IV formulations, and 7 to 10 days after initiation of the oral suspension formulation.4,15,16 Patients were excluded from this study if they did not have a steady-state plasma concentration drawn within the specified time frame or did not have a trough drawn during an inpatient hospital stay. Additionally, patients were excluded if they were switched to a different formulation of posaconazole before obtaining their initial trough plasma concentration. Patients included in this study were stratified based on those taking posaconazole for prophylaxis or treatment.
Data Collection and Analysis. Data were extracted from the electronic medical record to include: patient demographics, date of posaconazole initiation, date of initial trough drawn, primary diagnosis, laboratory values (e.g., serum creatinine, liver function tests [LFTs], posaconazole trough serum concentrations), posaconazole dosing information (e.g., dose, frequency, formulation), indication of breakthrough IFI while on prophylactic posaconazole, concomitant acid suppression received, and early discontinuation of therapy. Steady-state concentration was determined by subtracting the date of posaconazole initiation from the date of initial trough drawn. Data were analyzed using descriptive statistics.
Outcomes. The primary outcome was to determine the percentage of pediatric patients who achieved a prophylactic trough goal of ≥700 ng/mL or a treatment trough goal of ≥1000 ng/mL using the initial posaconazole dosing strategy. Of note, initial posaconazole dosing was based on clinician discretion as an official formulary dosing guideline did not exist during the study time period. Multiple secondary outcomes were assessed within this study, including the percentage of patients receiving prophylaxis who developed a breakthrough IFI, the number of dose modifications needed to achieve target trough concentrations, the final dose (in mg/kg/day) to achieve target trough concentrations, the percentage of patients with concomitant use of acid suppression, the percentage of patients who developed elevated LFTs while on therapy, and the percentage of patients who discontinued therapy for any reason.
Breakthrough IFI was evaluated as any patient with possible, probable, or proven fungal infection using definitions from the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG).17 The time frame observed for breakthrough IFI in this study was limited to the specific admission in which posaconazole was initiated for prophylaxis. The number of dose adjustments, assessed for each patient individually, was based on the number of dose adjustments made in response to a steady-state concentration. Concomitant use of acid suppressants was assessed because these agents can decrease absorption of posaconazole, and in turn decrease the plasma concentration. This was defined as any acid-suppressing agent ordered for administration during the same time period as posaconazole. Posaconazole has been observed to elevate LFTs, and discontinuation of medication should be considered if patients develop abnormal LFTs.4 Elevated LFTs, including aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, were defined as 3 times the upper normal limit based on the patient's age and sex.18
Results
Patient Characteristics. A total of 27 patients were included in the final analysis for the primary outcome, and their baseline characteristics are described in Table 1. There were 15 patients (55.5%) who reached the desired trough concentration with the initial dosing regimen. Only 5 of the 12 patients who did not meet the desired trough concentration had subsequent trough concentrations to assess. Of those 5 patients with subsequent trough concentrations, 1 to 3 dose modifications were required to achieve the desired trough. The 7 patients who did not receive additional trough concentrations were either discharged from the hospital and managed outpatient, switched to a different antifungal agent, or discontinued treatment after surgical management (Tables 2 and 3). There were 4 patients who were not on concomitant acid-suppressing agents in this study (Tables 2 and 3). Of those patients, half were on prophylactic dosing and half on treatment dosing. One patient in each of those groups had a desired trough concentration with their initial dosing regimen. The specific breakdown of agents for those on prophylaxis and treatment doses of posaconazole are described in Tables 2 and 3.
Table 1.
Baseline Characteristics (N = 27)
| Characteristic | Prophylaxis (n = 19) | Treatment (n = 8) |
|---|---|---|
| Age, n (%) | ||
| <13 yr | 4 (21.1) | 4 (50) |
| ≥13 yrs | 15 (78.9) | 4 (50) |
| Weight on admission, median (IQR), kg | 60 (42–76.5) | 43 (17.5–59.5) |
| Sex, n (%) | ||
| Male | 13 (68.4) | 5 (62.5) |
| Female | 6 (31.6) | 3 (37.5) |
| Primary diagnosis, n (%) | ||
| Cystic fibrosis | — | 1 (12.5) |
| Bone marrow transplant | 5 (26.3) | 2 (25) |
| Acutelymphoblastic leukemia | 3 (15.8) | — |
| Acute myeloid leukemia | 7 (36.8) | 4 (50) |
| Other | 4* (21.1) | 1† (12.5) |
| Acid suppression use, n (%) | ||
| Proton pump inhibitor | 2 (10.5) | 1 (12.5) |
| H2 receptor antagonist | 14 (73.6) | 4 (50) |
| Both | 1 (5.3) | 1 (12.5) |
| None | 2 (10.5) | 2 (25) |
| Posaconazole formulation, n (%) | ||
| Intravenous | 3 (15.7) | 2 (25) |
| Oral suspension | 3 (15.7) | 2 (25) |
| Delayed release | 13 (68.4) | 4 (50) |
* Burn, sickle cell disease, aplastic anemia, thoracic paraspinal myeloid sarcoma.
† Animalbite.
Table 2.
Patient-Specific Posaconazole Prophylaxis Dosing Information
| Patient Number | Age, yr (Weight, kg) | Starting Dose* and Frequency | Therapeutic Dose* and Frequency | Acid Suppression |
|---|---|---|---|---|
| Intravenous (n = 3) | ||||
| 21 | 1 (8) | 5.61 twice daily | 5.61 twice daily | None |
| 14 | 15 (55) | 5.45 daily | 5.45 daily | H2RA |
| 3 | 17 (60) | 5 daily | Not therapeutic; DC from hospital | PPI |
|
| ||||
| Oral suspension (n = 3) | ||||
| 46 | 1 (11) | 3.63 three times daily | 4.7 three times daily | H2RA |
| 32 | 14 (61) | 3.27 three times daily | Not therapeutic; switched to alternative tx | H2RA |
| 1 | 20 (83) | 2.41 three times daily | not therapeutic; switched to alternative tx | None |
|
| ||||
| Delayed-release tablets (n = 13) | ||||
| 36 | 6 (22) | 9 daily | 9 daily | H2RA |
| 34 | 8 (40) | 7.5 daily | 7.5 daily | H2RA |
| 28 | 13 (27) | 3.7 daily | 3.7 daily | H2RA |
| 39 | 14 (59) | 5 daily | 5 daily | PPI |
| 31 | 15 (44) | 6.8 daily | 6.8 daily | H2RA |
| 50 | 17 (136) | 2.2 daily | 2.2 daily | H2RA |
| 12 | 18 (116) | 2.59 daily | 1.73 twice daily | H2RA |
| 48 | 18 (89) | 3.3 daily | 3.3 daily | H2RA |
| 6 | 21 (55) | 5.45 daily | Not therapeutic; DC from hospital | H2RA |
| 16 | 21 (84) | 3.57 daily | 3.57 daily | H2RA |
| 25 | 21 (63) | 4.75 twice daily | 4.75 twice daily | H2RA |
| 29 | 21 (70) | 4.29 daily | 4.29 daily | H2RA and PPI |
| 55 | 21 (70) | 4.3 daily | 2.85 twice daily | H2RA |
DC, discharged; H2RA, H2-receptor antagonist; PPI, proton pump inhibitor; tx, treatment
* milligrams per kilogram.
Table 3.
Patient Specific Posaconazole Treatment Dosing Information
| Patient Number | Age, yr (Weight, kg) | Starting Dose* and Frequency | Therapeutic Dose* and Frequency | Acid Suppression |
|---|---|---|---|---|
| Intravenous (n=2) | ||||
| 13 | 1 (12) | 4.17 three times daily | Not therapeutic; DC from hospital | None |
| 47 | 5 (19) | 10.5 daily | 10.5 daily | H2RA |
|
| ||||
| Oral suspension (n=2) | ||||
| 19 | 3 (13) | 9.17 three times daily | 9.23 three times daily | H2RA |
| 2 | 8 (50) | 8 twice daily | 6 daily | PPI |
|
| ||||
| Delayed release tablets (n=4) | ||||
| 45 | 13 (78) | 3.8 daily | 6.4 daily | H2RA |
| 18 | 14 (73) | 4.1 daily | Not therapeutic; DC after surgical management | H2RA |
| 38 | 17 (36) | 8.3 daily | 8.3 given daily | H2RA and PPI |
| 7 | 19 (55) | 5.45 daily | 5.45 given daily | None |
DC, discharged; H2RA, H2 receptor antagonist; PPI, proton pump inhibitor
* milligrams per kilogram.
Dosing Information for All Patients. Most patients in this study received DR tablets (63%; n = 17). The Figure describes accurately collected trough concentrations (in nanograms per milliliter) after the first initial dosing regimen. The Figure also depicts whether the patient was initiated on posaconazole for the purpose of prophylaxis or treatment as well as their age (years). The average doses for reaching desired prophylactic and treatment trough serum concentrations with DR tablets were 5.5 mg/kg/day (range, 2.2–9 mg/kg/day) and 6.7 mg/kg/day (range, 5.4–8.3 mg/kg/day), respectively. There were 5 patients (18.5%) who received IV posaconazole, and the average dose for reaching desired prophylactic trough serum concentrations was 8.3 mg/kg/day (range, 5.4–11.2 mg/kg/day) and for treatment, only 1 patient who stayed on IV therapy achieved a desired trough serum concentrations with a dose of 10.5 mg/kg/day. There were 5 total patients (18.5%) receiving the oral suspension, with only 1 patient continuing the medication long enough to obtain a desired prophylactic trough serum concentration with a dose of 14.1 mg/kg/day. There were only 2 patients receiving the oral suspension for treatment purposes who had a trough serum concentration above the goal, using a dosing range of 16 to 27.7 mg/kg/day. Both patients were <13 years of age. Initial doses for those patients with repeated laboratory values for trough serum concentrations are described in Tables 2 and 3. Only 1 patient in on the oral suspension required a decrease in their initial dose based on a higher than desired trough serum concentration. Of note, there were 10 patients in this study who received a loading dose upon treatment initiation: 7 in the prophylaxis group and 3 in the treatment group. Overall, there were 5 patients who required a dose modification in our study and had subsequent trough concentrations drawn after modifications.
Figure.
First trough serum concentration values after initial posaconazole regimen by age.
Dosing Information for Patients Ages <13 Years. In patients ages <13 years (n = 8), most received IV and oral suspension (Tables 2 and 3). The 1 patient in this age group on oral suspension for prophylaxis obtained desired trough serum concentrations with a dose of 14.1 mg/kg/day. There was 1 patient who was initiated on IV posaconazole and achieved a desired treatment trough concentration with a dose of 10.5 mg/kg/day. This patient also was the only one to receive a loading dose in this age group. The 1 patient in this age group on IV posaconazole for prophylaxis achieved the desired trough serum concentration with a dose of 11.23 mg/kg/day.
Breakthrough IFI. There were 2 patients (10.5%) who were evaluated in our study for breakthrough IFI during their initial admission while on posaconazole prophylaxis. Both patients were classified as “possible” IFI according to the EORTC/MSG definitions based on their neutropenic state and hematologic malignancies, as well as computed tomography (CT) findings. Neither patient had mycologic evidence of IFI and both were treated empirically for their possible infections. One patient, a 20-year-old, was initiated on posaconazole oral suspension for prophylaxis at a dose of 7.3 mg/kg/day and received 10 days of therapy. Of note, this patient did not achieve target trough serum concentrations. Prior to the initiation of posaconazole, the patient did not have chest CT findings. On day 10, after multiple febrile episodes, CT findings described “bilateral patchy and nodular ground glass opacities with larger nodular opacities.” Bronchoscopy was completed but was inconclusive. This patient was subsequently switched to a different antifungal agent for treatment. The second patient, a 21-year-old, was initiated on posaconazole DR tablets at a dose of 4.3 mg/kg/day for prophylaxis and during admission experienced low-grade fevers and complained of cough. This patient did achieve target concentrations with their initial dosing regimen for prophylaxis, but subsequently had multiple changes in formulations during this admission because of an inability to take oral medications, and did not have consistent desired trough concentrations. Although this is noteworthy, it does not define a cause-and-effect relationship. Chest CT findings showed “basilar ground-glass opacities and nodules” after a month of prophylaxis. This patient was converted to empiric treatment with posaconazole, although no mycologic evidence was found.
Adverse Drug Reactions. Overall, 5 patients developed elevated LFTs while on posaconazole, with only 1 patient having to discontinue treatment. This patient was initiated on posaconazole for treatment of a fungal infection and had normal LFTs prior. After 5 days of posaconazole dosing, LFTs were elevated 3 times the upper limit of normal for the patient's age. On day 6 of posaconazole, a trough concentration was obtained and was higher than the goal value, with a result of 2976 ng/mL. Twenty-two days after stopping posaconazole, the patient's LFTs returned to baseline. It is possible that concomitant use of agents known to cause elevated LFTs contributed to this patient's discontinuation, and therefore posaconazole was not of sole responsibility. There were 7 patients who discontinued posaconazole (prophylaxis or treatment) early for elevated LFTs (n = 1), were cured with surgical management (n = 1), switched to a different antifungal agent (n = 3), or had withdrawal of care (n = 2).
Discussion
The results of this study analyze a population of 27 pediatric patients newly initiated on posaconazole for prophylaxis and treatment of IFI. Although 55% of these patients were able to reach desired trough serum concentrations with their initial dosing regimen, nearly half still required at least 1 dose increase. There were only 5 patients who received follow-up trough concentrations after changing their dose while inpatient. The other 7 patients either discontinued treatment early, switched to a different formulation, or discharged from the hospital prior to obtaining desired troughs. Although outpatient monitoring is feasible, patients could potentially have been sent home on subtherapeutic dosing regimens, thus increasing their risk of breakthrough IFI. It is also difficult to verify proper drug administration in the out-patient setting.
In this study, there were 2 patients who experienced breakthrough infections while on posaconazole prophylaxis, which is comparable to rates seen in previous literature.6,12,19,20 According to the EORTC/MSG definition, both patients were classified as “possible” infection as evidenced by their hematologic malignancies (both acute myeloid leukemia) and neutropenic status, as well as their CT findings. Neither patient had mycologic evidence and both patients were treated empirically for their possible infections with either posaconazole or voriconazole. Of the 5 patients who required dose changes and had subsequent trough concentrations, there were 3 patients who needed more than 1 change before reaching desired trough concentrations. Depending on the formulation, each dose modification has the potential to extend the time a patient is subtherapeutic by nearly a week while awaiting steady-state concentrations, potentially increasing their likelihood for developing a breakthrough IFI.
There were 4 patients in this study who were not on acid suppression agents. Of those 4 patients, half reached their desired trough concentration. Only 1 of the 5 patients on the oral suspension was not on acid suppression, and this patient did not meet their desired trough serum concentration. Therefore, it is difficult to distinguish whether this had much of an effect on the 45% of patients who did not meet desired trough concentrations.
Posaconazole oral suspension is currently not approved for patients ages <13 years. An increase in its use, as well as that of other formulations in younger patients, has prompted the need for more pharmacokinetic literature.4,10,20 In this study,20 8 patients were ages <13 years, and average doses of oral suspension for prophylaxis were comparable, although slightly higher than those previously reported in the literature, with some patients needing doses of 15 to 20 mg/kg/day. The youngest patient, who was 1 year of age, was given an oral suspension for prophylaxis and required a 40% dose increase from their initial regimen of 10 mg/kg/day before reaching desired trough concentrations. This showcases that younger patients may need larger doses of the oral suspension. Overall, the dosing required to achieve desired trough concentrations for both prophylaxis and treatment in younger patients on IV posaconazole were similar to previous studies, ranging from around 10.5 to 12 mg/kg/day for prophylaxis and treatment, respectively.21,22 The youngest patients in this study who were prescribed DR tablets were 6 and 8 years of age (Table 3) and were both initiated on posaconazole for prophylaxis. The 6-year-old patient needed 9 mg/kg/day (200 mg daily) to achieve desired trough concentrations, and the 8-year-old required 7.5 mg/kg/day (300 mg daily). This dosing was identical to another study that used a population pharmacokinetic model to determine dosing of DR tablets in high-risk patients.13
The findings of this study must be interpreted in light of some limitations. The retrospective design of this study and manual chart review did not allow for verification of whether doses of the oral suspension were administered with a fatty meal as recommended. Therefore, no assumptions can be made about the lack of absorption as it relates to subtherapeutic trough concentrations in this population. The oral suspension is frequently used in our pediatric population. However, only 3 patients in this study were on oral suspension, which is known for having the greatest variation in absorption because of its bioavailability, and therefore steady-state trough concentrations.23,24 This study did not focus on clinical outcomes data, and therefore coexisting medical conditions were not analyzed to address further concerns of absorption. The definition used for breakthrough IFI in this study limited the time frame to identifying breakthrough infections during only the initial admission in which the patient was started on posaconazole. This time frame varied greatly among patients in this study, from days to months. Patients who may have developed an infection after being discharged home on posaconazole prophylaxis were therefore not identified with this restriction. Previous studies have reported breakthrough IFI 100 days or greater after initiation of posaconazole prophylaxis. However, given the inability to guarantee strict adherence to posaconazole after discharge, it was determined classifying breakthrough IFI in this study could potentially be inflated if not limited to the initial admission.
Overall, 24 patients were excluded from this study because of inappropriate pharmacokinetic monitoring practices. There were 15 patients excluded from this study based on incorrect timing of collection or trough serum concentrations. Troughs were either obtained prematurely and doses modified based on non–steady-state concentrations, or troughs were obtained later than current recommendations and patients were discharged home before reaching target concentrations. Another 9 patients were excluded for changing formulations of posaconazole prior to obtaining steady-state concentrations with their initial dosing regimen. Many of these patients were changed to a different formulation without accounting for the appropriate change in timing of the trough concentration needed. Furthermore, 4 of the 7 patients needing dose adjustments after their initial dosing regimen were discharged home prior to obtaining adequate trough concentrations.
Based on the findings of this study, there is a wide range of posaconazole dosing among all age groups and available formulations. Although 55% of the patients in this study were able to reach desired trough concentrations, nearly half did not for various reasons. These data potentially validate the need for a pharmacist-driven posaconazole protocol aimed at providing uniformity of initiation doses for all ages and formulations given this complexity. This protocol would also standardize timing between initiation doses and obtaining steady-state trough concentrations and would potentially improve pharmacokinetic monitoring. Improving the process for monitoring posaconazole may theoretically decrease the number of dose changes required to reach the desired trough concentrations, decrease the number of patients discontinuing therapy, or decrease those switching to another antifungal agent.
Conclusion
The results of this study describe a single population of pediatric patients on posaconazole in which 55% were able to achieve target dose concentrations with the initial dosing strategy used. A small number of patients experienced breakthrough IFI in this study while on prophylaxis, and overall discontinuation rates were low. This study demonstrates the variability in the dosing of posaconazole tablets, suspension, and IV formulations in pediatric patients. Future research is needed to investigate the potential impact of pharmacist-driven posaconazole dosing protocols that seek to improve monitoring and decrease time to desired trough concentrations.
ABBREVIATIONS
- CT
computed tomography
- DR
delayed release
- EORTC/MSG
European Organization for Research and Treatment of Cancer/Mycoses Study Group
- FDA
US Food and Drug Administration
- IFI
invasive fungal infection
- IV
intravenous
- LFT
liver function tests
Footnotes
Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Ethical Approval and Informed Consent. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and have been approved by the Institutional Review Board at our institution Written informed consent was not required due to the retrospective nature of the study.
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