Posaconazole therapeutic drug monitoring in pediatrics: a single-center retrospective study

Abstract

Background

Invasive fungal infections are associated with high morbidity and mortality in immunosuppressed pediatric patients. Posaconazole is commonly used for both prophylaxis and treatment of invasive fungal infections. The study’s primary objective was to determine the percentage (%) of patients that achieved posaconazole therapeutic targets. The secondary objective was to evaluate the relationship between posaconazole exposure and clinical outcomes or toxicity.

Methods

This single-center retrospective study included pediatric patients from 1 month to 18 years who received posaconazole for prophylaxis fungal infections. Data were collected from the hospital’s electronic medical records and included age, gender, height, weight, laboratory values, dose, dosing frequency, trough concentrations, drugs interact with posaconazole. Primary outcomes included the percentage of patients who achieved target trough levels of posaconazole. We also looked at factors correlated to trough concentrations, which included: dose, age, weight, presence of drug interactions and laboratory values such aspartate transaminase (AST), alanine transaminase (ALT), and albumin levels. Secondary outcomes included the correlation between posaconazole trough concentrations, clinical or microbiologic outcomes, and toxicity.

Results

A total of 69 trough plasma concentrations were measured across 42 patients. Among these, 27 patients had a second trough level assessed. The mean concentration of the initial trough was 1.4 ± 1.3 mg/L (mean ± SD), with concentrations ranging from 0.2 to 6.2 mg/L. The mean concentration of the second trough was 0.99 ± 0.8 mg/L, ranging from 0.2 to 4.1 mg/L. For the initial trough concentrations, 59.5% fell within the therapeutic range. A total of 10 patients (23.8%) experienced adverse events that were attributed to posaconazole.

Conclusion

Posaconazole trough concentrations vary in pediatric patients and around half of the patients achieved therapeutic concentrations with initial doses with minimal adverse events reported.

Background

Invasive fungal infections (IFIs) remain a major cause of morbidity and mortality in immunosuppressed pediatric patients undergoing chemotherapy, hematopoietic stem cell transplantation (HSCT), or prolonged immunosuppressive therapy [1–3]. Antifungal prophylaxis is a cornerstone of supportive care, aiming to reduce IFIs-related morbidity and mortality, as the incidence of IFIs has historically shown a consistent upward trend in this vulnerable population [4–8]. Mortality rates have been reported to be as high as 67.6%, particularly among those pediatric patients with pre-engraftment neutropenia, severe graft-versus-host disease (GVHD), or a history of prior transplant [1, 2]. Therefore, timely initiation of effective antifungal prophylaxis is critical to improving survival outcomes [3, 9].

Posaconazole is a broad-spectrum triazole antifungal used in pediatric patients for the prophylaxis and treatment of IFIs, primarily caused by Aspergillus and Candida species. It reduces IFIs incidence and related mortality in high-risk immunocompromised populations [10–15]. Clinical data demonstrates that children with breakthrough IFIs during prophylaxis had posaconazole levels of 0.4 mg/L, significantly lower than those without infection (1.2 mg/L), underscoring a concentration-response relationship [11, 16]. Posaconazole exhibits complex pharmacokinetics, including high protein binding, nonlinear metabolism influenced by genetic polymorphisms, physiological factors, and formulation-dependent absorption leading to significant inter-individual variability [17–19]. It is primarily metabolized by hepatic UDP-glucuronidation (UGT1A4) through phase II glucuronidation, and is a known substrate for P-glycoprotein (P-gp) efflux making it susceptible to drug-drug interactions [18, 20, 21]. In addition to its complex pharmacokinetics, posaconazole has a narrow therapeutic index. Clinical studies in both adults and pediatric patients have shown that maintaining trough concentrations above 0.7 mg/L improves clinical outcomes, while concentrations ≥ 1.0 mg/L increase the probability of successful prophylaxis and treatment [22, 23]. However, concentration levels higher than 3.5 mg/L are associated with an increased risk of hepatotoxicity and QT prolongation [22–24]. These recommendations align with the Infectious Diseases Society of America guidelines, which emphasize the importance of therapeutic drug monitoring to optimize posaconazole efficacy and safety [25].

Posaconazole therapeutic drug monitoring (TDM) in critically ill pediatric patients is not well established, despite the drug’s narrow therapeutic range and considerable inter- and intra-individual variability in exposure. Factors such as altered physiology, inflammation, organ dysfunction, and polypharmacy commonly affect drug absorption and metabolism in this population, leading to subtherapeutic or potentially toxic levels. The purpose of this study was to describe posaconazole pharmacokinetic/pharmacodynamic (PK/PD) targets achieved and to evaluate the efficacy and safety of posaconazole for the pediatric population.

Methods

Study design and population

This single-center retrospective study was conducted in pediatric units at King Faisal Specialist Hospital and Research Centre. Eligible patients included pediatric patients from 1 month to 18 years who received oral posaconazole for antifungal prophylaxis and had at least one measured serum trough concentration according to the institutional protocol. Per protocol, posaconazole is used for acute leukemia high-risk for mold infection (expected neutropenia > 21 days) starting twenty-four hours after the last day of chemotherapy, and continued till neutrophil recovery (Absolute Neutrophil Count (ANC) > 0.5 × 10⁸). Additional indication included, allogeneic Stem Cell Transplantation (SCT) with Graft-Versus-Host Disease (GVHD) with patients grade II-IV acute GVHD, or extensive chronic GVHD requiring steroid and/or other immunosuppressive therapy. Duration of Posaconazole as prophylaxis is determined according to GVHD course/resolution and level of immunosuppression and steroid therapy patients receiving. Trough concentrations were obtained after ≥ 5 days of therapy initiation if duration is expected to continue more than 10 days. Therefore, all posaconazole trough levels were measured at steady state. Posaconazole dosing was determined based on the hospital’s institutional antifungal prophylaxis guidelines for posaconazole suspension as 200 mg oral three times daily and posaconazole delayed release oral tablet 300 mg every 12 h (two doses), followed by 300 mg oral every 24 h for children ≥ 13 years old. Doses for children < 13 years old are prescribed as weight-based dosing as the followings: 10 to < 12 kg: 90 mg twice daily for 2 doses, followed by 90 mg once daily, 12 to < 17 kg: 120 mg twice daily for 2 doses, followed by 120 mg once daily, 17 to < 21 kg: 150 mg twice daily for 2 doses, followed by 150 mg once daily, 21 to < 26 kg: 180 mg twice daily for 2 doses, followed by 180 mg once daily, 26 to < 36 kg: 210 mg twice daily for 2 doses, followed by 210 mg once daily, and 36 to ≤ 40 kg: 240 mg twice daily for 2 doses, followed by 240 mg once daily. Exclusion criteria include patients with missing posaconazole trough concentration during the study time period, patients received posaconazole for treatment of existing invasive fungal infections, or incomplete medical records. The study period was from January 2019 to March 2024. From January 2019 to July 2020, posaconazole levels were sent out to Bioscientia laboratory in Germany or Mayo Clinic Laboratories in the United States. Afterward, posaconazole drug levels were assayed in house at our institution. For all centers, the assay method was done using liquid chromatography tandem mass spectrometry (LC- MS/MS).

Data collection

Data were extracted from the hospital’s electronic medical records and included patients’ demographics, laboratory values, posaconazole dose, trough concentrations measured at steady state, and presence of neutropenia. We also collected all medications known to significantly interact with posaconazole including, ondansetron, omeprazole, amiodarone, aprepitant, clarithromycin, crizotinib, dasatinib, domperidone, acalabrutinib, sirolimus, rifabutin, ruxolitinib, carbamazepine, rifampine, methotrexate, citalopram, tacrolimus, imatinib, lacosamide, sodium bicarbonate, metoclopramide, oxybutynin, and phenobarbital. All patients included in this study received posaconazole for antifungal prophylaxis; no patients were treated for active fungal infection. Supratherapeutic posaconazole concentrations were defined as troughs (> 3.5 mcg/ml) and low concentrations is defined as troughs (< 0.7 mcg/ml). Dose adjustment was applied for patients with low and high trough posaconazole concentrations. Prophylaxis success was defined according to clinical, mycological, or radiologic responses, in conjunction with the treating physician’s clinical judgment.

Study outcomes

Primary outcomes included the percentage of patients who achieved therapeutic target trough levels of posaconazole. We also looked at factors correlated to trough concentrations, which included dose, age, weight, presence of drug interactions and laboratory values such as AST, ALT, C- reactive protein and albumin levels [9, 10]. Secondary outcomes included the correlation between posaconazole trough concentrations, and clinical or microbiologic outcomes and toxicity. For this outcome, we used the first trough concentration drawn at steady state for all patients. Posaconazole dose adjustments was made based on available hospital guidelines for therapeutic drug monitoring of antifungals. Clinical and microbiologic outcomes were evaluated for patients with prophylaxis or treatment. We examined the association between posaconazole trough concentrations and adverse effects, specifically neurological symptoms, liver injury, diarrhea, and acute kidney injury (AKI). Identification of posaconazole-related toxicity was based on clinician-documented assessments in the medical records, with laboratory data providing supporting evidence when relevant.

Statistical analysis

Baseline characteristics were analyzed using descriptive statistics. Quantitative variables were presented as mean ± standard deviation (SD). Categorical variables were summarized as frequencies and percentages. To identify factors significantly associated with posaconazole trough concentrations, multiple linear regression analysis was performed. Variables included in the regression model were: posaconazole dose, route, alanine transaminase (ALT), albumin, aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin, C-reactive protein (CRP), and the presence of drug interactions. Independent t-tests were used to compare clinical cure rates and the incidence of toxicity between groups. A p-value of < 0.05 was considered statistically significant. All statistical analyses were conducted using R statistical software.

Results

Clinical information

A total of 42 pediatric patients were included in the analysis, of whom 22 (52.4%) were female. The mean age was 11.9 (± 4.9) years, with corresponding mean weight, height, and body mass index (BMI) of 37.7 (± 21.1) kg, 137.3 (± 28.6) cm, and 21.8 (± 24.2) kg/m², respectively (Table 1). At baseline, 9 participants (21.4%) were neutropenic. Among the cohort, 20 patients (47.6%) received an initial dose consistent with current guideline recommendations. In contrast, 13 patients (30.9%) were prescribed subtherapeutic doses, while 9 patients (21.4%) received supratherapeutic doses exceeding recommended thresholds. Potential pharmacokinetic interactions involving posaconazole were identified in 29 patients (69.1%). Frequently implicated agents include ondansetron, omeprazole, aprepitant, sirolimus, ruxolitinib, tacrolimus, imatinib, lacosamide, sodium bicarbonate, and phenobarbital. Based on the nature of the interacting agents, 36 patients (85.7%) were receiving enzyme inducers, 4 (9.5%) enzyme inhibitors, and 1 (2.4%) both an inducer and an inhibitor. Posaconazole dosing was subsequently modified in response to these interactions and supra or subtherapeutic posaconazole drug levels. Baseline demographics and laboratory values are detailed in Tables 1 and 2.

Table 1.

Baseline characteristics of the study population

Characteristic	Mean ± SD
Age (years)	11.9 ± 4.9
Weight (kg)	37.7 ± 21.1
Height (cm)	137.3 ± 28.6
BMI	21.8 ± 24.2
Age Category, n (%)
1–18 (years)	41 (97.6%)
1 to 12 months	1 (2.4%)
Sex, n (%)
Male	20 (47.6%)
Female	22 (52.4%)
Neutropenia based on ANC at the beginning of treatment, n (%)
Yes	9 (21.4%)

ANC Absolute neutrophil count, BMI Body mass index, SD Standard deviation

Table 2.

Participants lab values at baseline

Laboratory Results	Mean ± SD
γ-GT (IU/L)	88.4 ± 204.2
ALT (IU/L)	35.3 ± 55.8
AST (IU/L)	28.9 ± 26.4
INR	1.2 ± 0.23
Total bilirubin (umol/L)	8.3 ± 6.3
Alkaline phosphatase (IU/L)	211 ± 161.6
Plasma albumin (g/L)	36.2 ± 4.4
WBC (10^9/L)	6.5 ± 8
ANC (10^9/L)	18.8 ± 27.7
CRP (mg/L)	43.1 ± 60.5
Procalcitonin (ng/ml)	0.8 ± 1.9
Aspergillus galactomannan	0.1 ± 0.2
1,3-β-D-Glucan (Fungitell)	53.5 ± 86

ALT Alanine aminotransferase, ANC Absolute neutrophil count, AST Aspartate transferase, BMI Body mass index, CRP C-reactive protein, GGT Gamma-glutamyl transferase, INR International normalized ratio, SD Standard deviation, WBC White blood count

Primary outcome

A total of 69 trough plasma concentrations were measured across 42 patients. Among these, 27 patients had a second trough level assessed. The mean concentration of the initial trough was 1.4 ± 1.2 mg/L (mean ± SD), with concentrations ranging from 0.2 to 6.2 mg/L. The mean concentration of the second trough was 0.99 ± 0.89 mg/L, ranging from 0.2 to 4.1 mg/L. Regarding the initial trough concentrations, 59.5% fell within the therapeutic range, whereas 4.7% were above and 35.7% were below this range. Among patients with a second trough measurement, 51.9% were within the therapeutic range, 44.5% were below it, and 3.7% were above it. Of the 16 patients whose initial trough levels were not within the therapeutic range, 11 received a dose adjustment and had a second trough measurement. Among these, only 4 patients (36.4%) achieved therapeutic concentrations after the intervention. For factors associated with posaconazole trough concentrations, only the dose was significantly correlated (R² = 0.1, P value < 0.05) (Table 3).

Table 3.

Posaconazole dosing and trough concentrations

Parameter	N (%) / Mean ± SD
Oral Route (Tablet)	27 (64.28)
First dose (mg/kg/day)	10.9 ± 6.8
First dose (mg/day)	215.3 ± 94.7
Second dose (mg/kg/day)	6.2 ± 8.4
Second daily dose (mg)	140.7 ± 142.1
Average trough for first dose (mg/L)	1.81 ± 1.2
Average trough for second dose (mg/L)	1.8 ± 1.4
Trough 1 (mg/L)	1.6 ± 1.3
Trough 2 (mg/L)	1.2 ± 1
Oral Route (Liquid)	15 (35.71)
First dose (mg/kg/day)	17.8 ± 5.4
First dose (mg/day)	319.9 ± 134.1
Second dose (mg/kg/day)	10.1 ± 11.1
Second dose (mg/day)	193.9 ± 226.5
Average trough for first dose (mg/L)	1.3 ± 1.3
Average trough for second dose (mg/L)	0.5 ± 0.6
Trough 1 (mg/L)	1 ± 1.3
Trough 2 (mg/L)	0.6 ± 0.5
First dose (mg/day) (N = 42)*	602.3 ± 177.7
Trough 1 (mg/L) (N = 42)*	1.4 ± 1.3
Less than the range (< 0.7 mg/L)	15 (35.7)
Within the range (0.7–3.5 mg/L)	25 (59.5)
More than the range (> 3.5 mg/L)	2 (4.8)
Second dose (mg/day) (N = 23)*	544.9 ± 181.6
Trough 2 (mg/L) (N = 27)*	0.99 ± 0.89
Less than the range (< 0.7 mg/L)	12 (44.5%)
Within the range (0.7–3.5 mg/L)	14 (51.9%)
More than the range (> 3.5 mg/L)	1 (3.7%)

*The total number of trough levels (including first and second trough levels) was 69 from 42 participants

Secondary outcome: clinical and toxic outcomes

A total of 10 patients (23.8%) experienced adverse events attributed to posaconazole therapy, as assessed by the treating clinicians. Reported toxicities included diarrhea (n = 4), acute kidney injury (AKI; n = 3), hepatotoxicity (n = 1), peripheral neuropathy (n = 1), QT interval prolongation (n = 1), and hypokalemia (n = 1). In some patients, more than one adverse event occurred. Despite these events, no breakthrough fungal infections were documented during the study period, suggesting that posaconazole maintained its prophylactic efficacy. The mean posaconazole trough concentration among patients who developed toxicities was 1.8 mg/L (± 1.7), compared to 1.3 mg/L (± 1.2) in those without documented adverse events. This difference was not statistically significant based on an independent t-test (p = 0.24). All adverse events were identified through clinician documentation and supported by relevant laboratory or diagnostic findings when available. Management strategies included dose modification, drug discontinuation, or substitution with an alternative antifungal agent, depending on the nature and severity of the event.

Discussion

In this study, we reported a total of 69 posaconazole trough plasma concentrations were assessed across 42 patients, with 27 patients undergoing a second trough level measurement. Only around half of initial troughs were within the therapeutic range, which indicates the importance of starting posaconazole at appropriate dosing, and the need of adjusting and monitoring posaconazole trough levels. Additionally, minimal side effects were reported with posaconazole use as only 23.8% of the patients experienced posaconazole-related toxicities, though none developed breakthrough fungal infections, indicating sustained prophylactic efficacy. Notably, the mean trough concentration in patients with toxicity was higher (1.8 ± 1.7 mg/L) than in those without toxicity (1.3 ± 1.2 mg/L), though the difference was not statistically significant (p = 0.24). Compared to prior studies, these findings align with existing evidence of substantial inter- and intra-patient variability in posaconazole pharmacokinetics. For instance, Du et al. reported that only 59.5% of pediatric hematology patients achieved target trough levels despite wide dosing ranges, identifying factors such as HSCT, diarrhea, and acid-suppressive therapy as contributors to low levels [26]. Similarly, Märtson et al. found persistent variability even with IV and modified-release tablet formulations, and like the present study, identified posaconazole dose as the sole significant predictor of plasma concentrations [27]. Another study by Lai et al., conducted a retrospective study of immunocompromised children < 13 years of age receiving posaconazole suspension prophylaxis at a starting dose of 5 mg/kg every 8 h showed that, mean posaconazole plasma concentration was 783.4 ng/mL (IQR 428.3–980 ng/mL) and the percentage of patients with a posaconazole plasma concentration ≥ 700 ng/mL was 47.9%. However, the breakthrough invasive fungal infection rate was low as 4.3% [28]. These studies confirm that therapeutic drug monitoring (TDM) remains essential due to the unpredictable absorption and exposure patterns, even with more advanced formulations.

Absorption of posaconazole from oral suspension formulations is highly dependent on gastric acidity and food intake, leading to subtherapeutic levels particularly in pediatric and critically ill patients [29]. A recent study by Du et al. in pediatric hematology patients indicates that posaconazole oral suspension exhibits substantial inter-individual variability. Only 59.5% of children under 13 years achieved the recommended target trough concentration of ≥ 0.7 mg/L despite wide dosing ranges (4.2–51.2 mg/kg/day). Multivariate regression analysis identified several factors independently associated with subtherapeutic concentrations including HSCT, diarrhea, hypoalbuminemia, high-dose methylprednisolone (≥ 0.7 mg/kg/day), and concomitant administration of omeprazole or famotidine. Importantly, increasing daily posaconazole doses beyond 18 mg/kg/day did not improve exposure and was negatively correlated with plasma concentrations, consistent with the known saturable absorption characteristics of the suspension formulation [26]. The tablet formulation provides improved and more consistent absorption, however, routine TDM is still necessary to account for inter- and inter-individual variability [30, 31]. Intravenous (IV) posaconazole formulations provide the most reliable drug exposure but are typically reserved for patients who cannot tolerate oral formulations [32–34]. A clinical study by Märtson et al. involving patients receiving posaconazole modified-release tablets or IV formulations demonstrated persistent inter- and intra-patient variability in drug concentrations with 36% of measured trough levels falling outside the defined therapeutic window despite standardized dosing. Moreover, longitudinal analysis revealed that among all tested confounding variables, including liver function markers (ALT, AST, ALP, γ-GT, bilirubin), C-reactive protein, age, gender, and administration route, only the posaconazole dose had a statistically significant effect on plasma concentration [27]. Omar et al. obtained data from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. Posaconazole pharmacokinetics were best described by a one-compartment model with lag time and nonlinear bioavailability, with substantial interindividual variability observed. Across all simulated dosing strategies, the probability of target attainment remained below 85%, indicating suboptimal exposure, and highlighting the impact of clinical factors on drug exposure and target attainment including patients with diarrhea or receiving proton pump inhibitors [35]. This highlights the unpredictable nature of posaconazole pharmacokinetics even with newer formulations and supports the continued use of TDM to optimize exposure and improve clinical decision-making.

Therapeutic drug monitoring (TDM) of posaconazole in critically ill pediatric patients remains an area with significant knowledge gaps, largely due to the considerable variability in drug exposure observed in this population. Our initial findings mirror previous reports showing that some patients fail to achieve the recommended therapeutic trough concentrations despite guideline-based dosing [16, 26, 27]. This variability is likely multifactorial, influenced by altered gastrointestinal function, inflammation, hypoalbuminemia, and polypharmacy common in critically ill children. Posaconazole’s complex pharmacokinetics characterized by high protein binding, saturable absorption, and susceptibility to drug interactions further complicate dosing. The frequent presence of drug interactions with posaconazole among our patients reflects this challenge and aligns with earlier studies highlighting significant drug-drug interactions affecting posaconazole plasma levels. Notably, dose increases did not consistently translate into higher drug concentrations, consistent with saturable absorption reported in pediatric hematology patients [17–21, 33]. These findings underscore the unpredictable pharmacokinetic behavior of posaconazole and reinforce the necessity of routine TDM to tailor dosing strategies individually.

Limitations

The limitations of this study include a relatively small sample size and limited follow-up for long-term outcomes. In addition, adverse events were based on clinician documentation without the use of standardized toxicity grading systems, which may have resulted in underreporting or inconsistent attribution. Potential confounding factors such as food intake, gastrointestinal status, and posaconazole oral formulation type were not uniformly controlled, potentially affecting the observed variability in drug levels. Notably, some patients receiving the tablet formulation were instructed to crush and dissolve the tablets, which could have altered bioavailability and drug concentrations. Although regression and stratified analyses by formulation would have been valuable to better delineate pharmacokinetic differences, these analyses were not feasible due to the limited sample size.

Conclusion

Posaconazole trough concentrations vary in pediatric patients and around half of the patients achieved therapeutic concentrations with initial doses with minimal adverse events reported.

Authors’ contributions

KT and AS were responsible for the organization and coordination of the study. RM and HH were responsible for the data collection. AB and AS were responsible for the data analysis. All authors developed the study design, contributed to the writing of the final manuscript, and approved the final version of the manuscript.

Funding

Not applicable, and there was no funding provided.

Data availability

The authors had full access to all the data in the study and take responsibility for the confidentiality and integrity of the data and the accuracy of the data analysis. Data analysed and generated are provided within this manuscript. The full datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Human Ethics and Consent to Participate declarations is not applicable. Given the nature of this study, informed consent was not required by our institution review board (IRB). Therefore, waiver of informed consent was obtained. The study was submitted to the office of research affairs (ORA), reviewed by the research ethics committee (REC), and approved by the institutional review board (IRB) at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia. IRB# 2241136. Data collection and analysis were performed in accordance with the institutional review board guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.