Therapeutic drug monitoring of posaconazole oral suspension in paediatric hematology patients under 13 years of age

Introduction

Invasive fungal diseases (IFDs) are important causes of morbidity and mortality in pediatric patients receiving intensive chemotherapy or those undergoing hematopoietic stem-cell transplantation (HSCT) (1-3). Systemic antifungal prophylaxis has been shown to reduce the incidence of IFDs (4,5). Posaconazole is a second-generation, broad-spectrum triazole that is recommended for the prevention and treatment of various IFDs (3,6,7).

The available formulations of posaconazole include an intravenous solution and three different oral formulations (oral suspension; delayed-release tablets; and delayed-release powder for oral suspension) (8). The novel delayed-release oral suspension has been approved for use in children over 2 years of age (9), but it is still not available in China. Although the oral suspension is not approved for use in children under 13 years of age, available evidence supports its use in patients aged 1 month to 12 years (3). Therefore, in China, infants and young children often receive the oral suspension product as a primary prophylaxis against IFDs due to their inability to swallow delayed-release tablets (10).

Previous studies have shown that posaconazole oral suspension has significant bioavailability and individual variability issues in clinical practice. As already widely reported in adults, several factors contribute to this large variability, including dietary status, gastric pH and motility, drug-drug interactions, and patient pathophysiological status [diarrhea, vomiting and gastrointestinal graft versus host disease (GI GVHD)] (11-14). Owing to the high individual variability, therapeutic drug monitoring (TDM) and timely adjustment of the dosing regimen to achieve the recommended target steady-state trough posaconazole concentration for effective IFD prophylaxis (≥0.7 µg/mL) or treatment (≥1.0–1.25 µg/mL) are recommended for patients receiving posaconazole suspension (15-17). The incidence of breakthrough IFDs can be significantly reduced by gradual dose adjustments in patients with low trough concentrations after posaconazole TDM (18).

Despite currently being unlicensed for use in children younger than 13 years of age, there are a few reports of off-label posaconazole suspension use in this population based on the favorable efficacy and safety of IFD prophylaxis in adults (19-22). Based on the extrapolation of the recommended prophylactic dosage in adults, these studies showed that children had highly variable posaconazole exposure. Multiple covariates significantly affect the absorption of posaconazole, thus making target concentration attainment challenging (22). TDM should be considered to ensure adequate posaconazole exposure (21). Given that little information is available, further attention to posaconazole exposure in this population remains imperative.

Therefore, the primary objective of this study was to describe posaconazole concentrations in pediatric patients aged younger than 13 years receiving posaconazole oral suspension and evaluate factors that may potentially affect posaconazole steady-state trough concentrations in this patient cohort. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-400/rc).

Methods

Patients and data collection

This retrospective, observational, single-center study was conducted at the Children’s Hospital of Soochow University and reviewed by the Ethics Committee of the Children’s Hospital of Soochow University (No. 2023CS157) and individual consent for this retrospective analysis was waived. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Patients receiving oral posaconazole suspension for IFD prophylaxis from January 2020 to July 2022 were included if they met the following criteria: aged younger than 13 years; patients with trough concentrations measured prior to steady-state concentrations (posaconazole administered for ≥7 days); and had ≥2 posaconazole concentrations. Patients that did not meet the inclusion criteria or had missing data were excluded.

Patient data were extracted from electronic medical records and laboratory reports, which contained demographic data (age, sex, weight, etc.) as well as information regarding the disease diagnosis and treatment, posaconazole dosing regimen and concentration monitoring, the use of concomitant medications that could potentially interfere with posaconazole absorption [proton pump inhibitors (PPIs); histamine H₂ antagonists (H₂As); and intermediate or high-dose methylprednisolone (defined as ≥0.7 mg/kg/day)] (23), clinical characteristics (the occurrence of vomiting, diarrhea, and GI GVHD and fasting or nasogastric tube feeding) during posaconazole sampling and biochemical parameters (serum albumin, alanine aminotransferase and bilirubin levels).

Posaconazole TDM

During posaconazole dosing, concentration monitoring and dose adjustments were routinely performed during inpatient and outpatient visits to ensure that target concentrations were achieved according to clinician preference. Serum samples to determine the posaconazole steady-state trough concentration were collected prior to providing the next dose of the drug. Posaconazole concentrations were determined in an external laboratory (The First Hospital of Soochow University, Suzhou, China). This laboratory used a validated liquid chromatography-tandem mass spectrometry assay, which has a linear range of 0.1–10 µg/mL, to measure posaconazole concentrations (24).

Statistical analysis

Continuous variables were expressed as medians, ranges and 25th–75th interquartile ranges (IQRs). Categorical variables were expressed as numbers (%). Univariate and multivariate linear mixed-effect models (with a random effect for patients accounting for correlations among repeated measurements of the same individuals) were used to identify factors that contributed to the variability in posaconazole steady-state trough concentrations. The effect of dosage regimen on posaconazole concentration was examined using the dosage range group with the highest rate of concentration attainment as the reference. All variables with a P value <0.1 in the univariate analysis were included in the multivariable stepwise backward analysis. A P value <0.05 was considered statistically significant. Statistical analyses were conducted and results were plotted using R 4.2.0 and GraphPad Prism 8.0.1, respectively.

Results

Patient characteristics

A total of 134 children who met the inclusion criteria were included in this study. Patient demographics, clinical characteristics and posaconazole treatment are summarized in Table 1. The median age was 6.8 (range, 0.4–12.9) years, with 61.4% of the patients being boys. The median weight was 20.3 (range, 7.0–76.0) kg. The predominant disease diagnosis was acute myeloid leukemia (31.1%), followed by aplastic anemia (22.0%) and acute lymphoblastic leukemia (18.9%). About 93.9% of the patients underwent HSCT, and 6.1% of the patients received chemotherapy.

Posaconazole dosing regimen and trough concentrations

Posaconazole was dosed two to four times per day, with slightly more than half of the patients (56.1%) using a daily regimen of three times per day. The median dosage of posaconazole by standardized body weight was 14.2 (range, 4.2–51.2) mg/kg/day (maximum starting dose of 200 mg/dose). A total of 922 posaconazole trough samples from 132 children were included in the analysis. A median of 4 (range, 2–23) samples were collected per patient. The majority of the 922 samples were from outpatients (67.6%). The overall median concentration was 0.81 (range, 0.05–4.5) µg/mL, of which 9 samples were counted as 0.05 µg/mL because they were below the limit of quantification (0.1 µg/mL). A total of 59.5% (549/922) of the samples reached the target level of 0.7 µg/mL for posaconazole prophylaxis (Figure 1). Intra- and interpatient variability was apparent among patients receiving 12 (range, 11–13) mg/kg/day of posaconazole suspension who had eight or more sample measurements (Figure 2).

Figure 1 Distribution of posaconazole trough concentrations at steady-state in 132 children under 13 years of age (n=922).

Figure 2 Intra- and interindividual variability of trough concentrations in 8 children receiving 12 (range, 11–13) mg/kg/day of posaconazole suspension. Each child had 8 or more samples. The graph shows the median with the interquartile range.

The distribution of posaconazole concentrations under different dosage regimens is shown in Figure 3. Among all seven dosage ranges, the percentage of patients who achieved the target level of 0.7 µg/mL ranged from 44.6% to 76.8%, with the lowest proportion in patients receiving >25 mg/kg/day and the highest proportion in patients receiving 18 (range, 17–19) mg/kg/day.

Figure 3 Distribution of posaconazole trough concentrations at steady-state concentrations under different dosage regimens. Boxes represent medians with interquartile ranges, and whiskers represent the 5th and 95th percentiles. Outliers are not shown. The red dashed line represents the target concentration (0.7 µg/mL) of posaconazole for antifungal prophylaxis.

Factors related to posaconazole trough concentrations

Univariate and multivariate mixed-effect linear regression analyses of the clinical variables associated with posaconazole steady-state trough concentrations are reported in Table 2. Multivariate analysis revealed significant positive correlations between albumin levels (P=0.004) and weight (P<0.001) and posaconazole concentrations. Conversely, treatment with HSCT (P=0.004), the occurrence of diarrhea (P=0.003), and the coadministration of omeprazole (P<0.001), famotidine (P=0.001) and methylprednisolone (dosage ≥0.7 mg/kg/day) (P=0.006) were associated with significantly reduced posaconazole concentrations. Taking the daily dosage of 18 (range, 17–19) mg/kg/day as a reference, all three groups with dosages below 18 mg/kg/day had a significant negative association with posaconazole concentrations. Moreover, doses higher than 18 (range, 17–19) mg/kg/day did not show a trend toward increased posaconazole concentrations. In contrast, a negative correlation with concentrations at a dosage of 21 (range, 20–22) mg/kg/day was statistically significant (P=0.046).

Discussion

Data on the clinical use of oral posaconazole suspension in pediatric patients remain limited to date, especially in children younger than 13 years of age. The limited reports exploring the optimal dosing regimen for posaconazole application in the pediatric population suggest that the proportion of patients achieving the target concentration with different dosage regimens remains low (19-22). Similar to these reports, we observed that 59.5% of pediatric patients (N=132) achieved the target concentration (0.7 µg/mL) with oral posaconazole suspension. The identification of clinical factors associated with a low target posaconazole concentration attainment rate is of great clinical concern, as suboptimal exposure may be associated with an attendant risk of breakthrough IFDs or therapeutic failure (11,25,26).

In the present study, there was a wide variation in the dosage of posaconazole suspension, ranging from 4.2 to 51.2 mg/kg/day, with a median value of 14.2 mg/kg/day. Therefore, we stratified the dosages to assess the effect of different dosage ranges on posaconazole concentrations. As shown in Figure 3, the highest proportion of target attainment (76.8%) was achieved in patients receiving 18 (range, 17–19) mg/kg/day. Taking 18 mg/kg/day as the reference, multivariate analysis showed that all other dosage regimens below 18 (range, 17–19) mg/kg/day had a significant negative correlation with posaconazole concentrations (Table 2).

In children under 13 years of age, the dosage recommendation for posaconazole is unclear. Based on extrapolation of the recommended prophylactic dosage of 600 mg/day in adults, corresponding to 10–12 mg/kg/day for an adult weighing 50–60 kg, Döring et al. (19) reported that the initial dosing strategy of 12 mg/kg/day resulted in a higher posaconazole trough concentration than the dosing strategy of 10 mg/kg/day (median 0.383 vs. 0.134 µg/mL) in children under 12 years of age, and as seen in both groups, the trough levels were lower than the target level (0.7 µg/mL). In the study by Lai et al. (22), an increase in the initial dosage to 15 mg/kg/day (maximum dose of 200 mg/dose) resulted in less than half (47.9%) of the immunocompromised children under 13 years of age achieving the target level. Therefore, higher initial dosing strategies of ≥20 mg/kg/day are recommended and expected to ensure adequate exposure (27,28).

However, we noted that with increasing daily doses, higher posaconazole concentrations were not observed. Conversely, at a dosage of 21 (range, 20–22) mg/kg/day, the posaconazole concentration showed a trend toward significantly lower concentrations compared to the dosage of 18 (range, 17–19) mg/kg/day (P=0.046, Table 2). This may be because posaconazole suspensions are characterized by saturable absorption in addition to the dose-dependent profile. This has been demonstrated in adults, where increasing the posaconazole suspension dose beyond 800 mg/day did not appear to result in consistent increases in the trough concentration (29,30). In the largest population pharmacokinetic study in children to date, it was also shown that increasing the posaconazole dose above 200 mg was also ineffective at increasing the concentrations (31).

Therefore, a dose regimen of 18 (range, 17–19) mg/kg/day would be more appropriate for the off-label use of posaconazole suspension in children, which would allow a higher percentage (76.8%) of children to achieve the effective prophylactic target concentration. Dosage regimens below 18 (range, 17–19) mg/kg/day all showed lower concentration achievement rates (Figure 3). Notably, dosage regimens higher than 18 (range, 17–19) mg/kg/day did not achieve increased concentrations. The guidelines newly published by the 8th European Conference on Infections in Leukaemia (ECIL-8) also suggested that the initial dosage of posaconazole suspension in patients aged 1 month to 12 years be 6 mg/kg three times daily (18 mg/kg/day), with a recommended target trough concentration of ≥0.7 µg/mL by TDM (3).

In addition to the dosage regimen affecting the posaconazole concentration, we also observed significantly lower posaconazole concentrations in pediatric patients with low body weight who were undergoing HSCT and had diarrhea, low albumin levels, and concomitant PPI (omeprazole), H₂A (famotidine), and steroid use (≥0.7 mg/kg/day of methylprednisolone) (Table 2). The first retrospective study (N=70) to analyze covariates affecting the absorption of posaconazole suspensions in children aged <13 years had findings similar to ours, with children with HSCT having lower trough concentrations (0.57 vs. 0.86 µg/mL, P=0.02) and being less likely to reach the target concentration (≥0.7 µg/mL) compared with children not receiving HSCT (14.7% vs. 85.3%, P=0.02) (22).

Patients with diarrhea were more likely to have low posaconazole exposure, which has been previously reported in studies of adults (14,32) and pediatric patients (31). This is because diarrhea increases gastrointestinal emptying with a decreased gastrointestinal residence time, thereby decreasing absorption.

Posaconazole is a highly protein-bound drug (>98% is primarily bound to albumin). Small changes in protein binding can significantly affect the free fraction of a highly protein-bound drug (33). In this study, lower posaconazole concentrations were observed with decreasing albumin concentrations, which is different from that observed in a previous pediatric population (34), and furthermore, other studies have not considered the effect of this covariate (22,31). Low albumin levels were shown to be a risk factor for suboptimal exposure to posaconazole in a study of adults receiving posaconazole delayed-release tablets (P=0.001) (32). This effect may be explained by the increasing concentration of the free fraction of posaconazole as albumin decreases, thus increasing the distribution of the free fraction from the blood to peripheral tissues, and increasing the amount of posaconazole that is cleared from the blood, leading to a decrease in the total drug concentration (33). Notably, increased albumin loss due to diarrhea likely leads to a further reduction in absorption and results in subtherapeutic trough concentrations (32).

Regarding drug-drug interactions, the concomitant use of PPIs (31,34) also has a negative impact on the bioavailability of posaconazole suspension in pediatric patients (22,31,34,35), which is consistent with the findings of our study. A population pharmacokinetic analysis in children (N=117) (31) showed that the bioavailability of posaconazole suspension was reduced by 42% with concomitant PPI use. Moreover, there is insufficient therapeutic target concentration attainment even at the highest feasible dose of posaconazole with the occurrence of diarrhea and/or PPI administration (31). In this study, the coadministration of H₂As (famotidine) was also found to be negatively associated with posaconazole concentrations, although the potential effect of this coadministration was not found in some other studies, probably due to the small number of patients using H₂As in those investigations and the weaker acid-suppressive capacity of H₂As compared to PPIs (22,31). Posaconazole is primarily metabolized by UDP-glucuronosyltransferase (UGT) 1A4. In a retrospective analysis conducted among adults, the combined use of intermediate or high-dose steroids (≥0.7 mg/kg/day) were found to be significantly associated with decreased trough concentrations of posaconazole delayed-release tablets (P=0.02). This effect, which was also observed in our analysis, may be attributed to the fact that hormones accelerate the metabolism of posaconazole by upregulating the activity of the UGT1A4 enzyme, thus leading to a reduction in its concentration (23).

Considering the need for disease treatment, complete exclusion of these risk factors for achieving posaconazole concentrations is clearly not possible, and the presence of these factors that may interfere with posaconazole concentrations in children suggests that clinicians should consider shifting to other antifungal infection strategies. Alternatively, the delayed-release tablet formulation of posaconazole may be another good option for children capable of swallowing tablets because of the improved absorption and increased bioavailability compared with the oral suspension (36-38). Furthermore, we expect that the new suspension formulation of posaconazole in oral powder will also be available for use in Chinese children. This formulation, with its dosage flexibility and the improved absorption characteristics of delayed-release tablets, will enable a higher proportion of children to reach effective target concentrations (39).

There are some limitations in the present study. First, it was a single-center retrospective observational study. Moreover, genetic factors that could influence posaconazole concentrations were not considered, as the UGT1A4*3 polymorphism has been found to be an independent risk factor for poor absorption of oral posaconazole suspension in patients with hematological malignancies (40).

Conclusions

In this study with the largest real-world dataset including children aged <13 years to date, we found that there are still large individual variations in the dosage regimens of oral posaconazole suspension, and the resultant posaconazole serum concentrations, and achieving target concentrations remains challenging. The results showed that an initial daily dosage regimen of 18 (range, 17–19) mg/kg/day would be more appropriate, allowing a higher proportion (76.8%) of children to achieve the recommended target concentration for effective prophylaxis (≥0.7 µg/mL). It is worth noting that higher dose regimens do not necessarily yield higher serum concentrations. In addition, factors such as albumin levels, body weight, HSCT, diarrhea, and concomitant medication use (omeprazole, famotidine, and methylprednisolone) had significant effects on posaconazole trough concentrations. TDM may be useful for identifying suboptimal exposure and making timely dose adjustments.

Acknowledgments

Funding: This study was supported by the Heng-rui Hospital Pharmacy Research Fund Program of Jiangsu Pharmaceutical Association (No. H202131); and the Project of Science and Technology Development Plan of Suzhou (No. SKYD2022123).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-400/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-400/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-400/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-400/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of the Children’s Hospital of Soochow University (No. 2023CS157) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002;100:4358-66. [Crossref] [PubMed]
2. Lehrnbecher T, Fisher BT, Phillips B, et al. Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients. J Clin Oncol 2020;38:3205-16. [Crossref] [PubMed]
3. Groll AH, Pana D, Lanternier F, et al. 8th European Conference on Infections in Leukaemia: 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation. Lancet Oncol 2021;22:e254-69. [Crossref] [PubMed]
4. Castagnola E, Rossi MR, Cesaro S, et al. Incidence of bacteremias and invasive mycoses in children with acute non-lymphoblastic leukemia: results from a multi-center Italian study. Pediatr Blood Cancer 2010;55:1103-7. [Crossref] [PubMed]
5. Döring M, Eikemeier M, Cabanillas Stanchi KM, et al. Antifungal prophylaxis with posaconazole vs. fluconazole or itraconazole in pediatric patients with neutropenia. Eur J Clin Microbiol Infect Dis 2015;34:1189-200. [Crossref] [PubMed]
6. Dadwal SS, Hohl TM, Fisher CE, et al. American Society of Transplantation and Cellular Therapy Series, 2: Management and Prevention of Aspergillosis in Hematopoietic Cell Transplantation Recipients. Transplant Cell Ther 2021;27:201-11. [Crossref] [PubMed]
7. Panagopoulou P, Roilides E. Evaluating posaconazole, its pharmacology, efficacy and safety for the prophylaxis and treatment of fungal infections. Expert Opin Pharmacother 2022;23:175-99. [Crossref] [PubMed]
8. Groll AH, Körholz K, Holterhus M, et al. New and emerging options for management of invasive fungal diseases in paediatric patients. Mycoses 2024;67:e13654. [Crossref] [PubMed]
9. FDA. 2021. Noxafil Powder Mix for delayed-release oral suspension. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214770Orig1s000Approv.pdf. FDA, Silver Spring, MD.
10. Working Group of Expert Consensus on Clinical Use of Posaconazole. Expert consensus on clinical use of posaconazole (2022 edition). Chinese Journal of Clinical Infectious Diseases 2022;15:321-33.
11. Dolton MJ, Ray JE, Chen SC, et al. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother 2012;56:5503-10. [Crossref] [PubMed]
12. Heinz WJ, Cabanillas Stanchi KM, Klinker H, et al. Posaconazole plasma concentration in pediatric patients receiving antifungal prophylaxis after allogeneic hematopoietic stem cell transplantation. Med Mycol 2016;54:128-37. [Crossref] [PubMed]
13. Cojutti P, Candoni A, Simeone E, et al. Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia: dose intensification coupled with avoidance of proton pump inhibitors is beneficial in shortening time to effective concentrations. Antimicrob Agents Chemother 2013;57:6081-4. [Crossref] [PubMed]
14. Dolton MJ, Brüggemann RJ, Burger DM, et al. Understanding variability in posaconazole exposure using an integrated population pharmacokinetic analysis. Antimicrob Agents Chemother 2014;58:6879-85. [Crossref] [PubMed]
15. Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1-e60. [Crossref] [PubMed]
16. Ashbee HR, Barnes RA, Johnson EM, et al. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014;69:1162-76. [Crossref] [PubMed]
17. Maertens JA, Girmenia C, Brüggemann RJ, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother 2018;73:3221-30. [Crossref] [PubMed]
18. Wang S, Li C, Dong Y, et al. Approaches for posaconazole therapeutic drug monitoring and their clinical benefits. Eur J Clin Pharmacol 2024;80:1845-55. [Crossref] [PubMed]
19. Döring M, Müller C, Johann PD, et al. Analysis of posaconazole as oral antifungal prophylaxis in pediatric patients under 12 years of age following allogeneic stem cell transplantation. BMC Infect Dis 2012;12:263. [Crossref] [PubMed]
20. Vanstraelen K, Colita A, Bica AM, et al. Pharmacokinetics of Posaconazole Oral Suspension in Children Dosed According to Body Surface Area. Pediatr Infect Dis J 2016;35:183-8. [Crossref] [PubMed]
21. Jancel T, Shaw PA, Hallahan CW, et al. Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review. J Clin Pharm Ther 2017;42:75-9. [Crossref] [PubMed]
22. Lai T, Alffenaar JW, Kesson A, et al. Evaluation of target attainment of oral posaconazole suspension in immunocompromised children. J Antimicrob Chemother 2020;75:726-9. [Crossref] [PubMed]
23. Cojutti PG, Candoni A, Lazzarotto D, et al. Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies. Br J Clin Pharmacol 2018;84:2544-50. [Crossref] [PubMed]
24. Jin HB, Dong J, Ding YD. Determination of posaconazole’s concentration in plasma by UPLC-MS-MS. Chinese Journal of Clinical Pharmacology 2019;35:3241-3.
25. Krishna G, Martinho M, Chandrasekar P, et al. Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease. Pharmacotherapy 2007;27:1627-36. [Crossref] [PubMed]
26. Cattaneo C, Panzali A, Passi A, et al. Serum posaconazole levels during acute myeloid leukaemia induction therapy: correlations with breakthrough invasive fungal infections. Mycoses 2015;58:362-7. [Crossref] [PubMed]
27. Bernardo VA, Cross SJ, Crews KR, et al. Posaconazole therapeutic drug monitoring in pediatric patients and young adults with cancer. Ann Pharmacother 2013;47:976-83. [Crossref] [PubMed]
28. Mathew S, Kussin ML, Liu D, et al. Retrospective Analysis of Posaconazole Suspension Dosing Strategies in a Pediatric Oncology Population: Single-Center Experience. J Pediatric Infect Dis Soc 2017;6:e149-51. [Crossref] [PubMed]
29. Krishna G, Moton A, Ma L, et al. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 2009;53:958-66. [Crossref] [PubMed]
30. Jeong W, Snell GI, Levvey BJ, et al. Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma concentrations. J Antimicrob Chemother 2018;73:748-56. [Crossref] [PubMed]
31. Boonsathorn S, Cheng I, Kloprogge F, et al. Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children. Clin Pharmacokinet 2019;58:53-61. [Crossref] [PubMed]
32. Tang LA, Marini BL, Benitez L, et al. Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother 2017;72:2902-5. [Crossref] [PubMed]
33. Veringa A, Sturkenboom MGG, Dekkers BGJ, et al. LC-MS/MS for Therapeutic Drug Monitoring of anti-infective drugs. TrAC Trends in Analytical Chemistry 2016;84:34-40.
34. Jia M, Zhang Q, Qin Z, et al. Dose Optimisation of Posaconazole and Therapeutic Drug Monitoring in Pediatric Patients. Front Pharmacol 2022;13:833303. [Crossref] [PubMed]
35. Vicenzi EB, Calore E, Decembrino N, et al. Posaconazole oral dose and plasma levels in pediatric hematology-oncology patients. Eur J Haematol 2018;100:315-22. [Crossref] [PubMed]
36. Döring M, Cabanillas Stanchi KM, Queudeville M, et al. Efficacy, safety and feasibility of antifungal prophylaxis with posaconazole tablet in paediatric patients after haematopoietic stem cell transplantation. J Cancer Res Clin Oncol 2017;143:1281-92. [Crossref] [PubMed]
37. Mauro M, Colombini A, Perruccio K, et al. Posaconazole delayed-release tablets in paediatric haematology-oncology patients. Mycoses 2020;63:604-9. [Crossref] [PubMed]
38. Tragiannidis A, Herbrüggen H, Ahlmann M, et al. Plasma exposures following posaconazole delayed-release tablets in immunocompromised children and adolescents. J Antimicrob Chemother 2019;74:3573-8. [Crossref] [PubMed]
39. Winchell G, de Greef R, Ouerdani A, et al. A population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia. Antimicrob Agents Chemother 2024;68:e0119723. [Crossref] [PubMed]
40. Suh HJ, Yoon SH, Yu KS, et al. The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension. Antimicrob Agents Chemother 2018;62:e02230-17. [Crossref] [PubMed]