Evaluation of target attainment of oral posaconazole suspension in immunocompromised children

Abstract

Background

Posaconazole is a broad-spectrum antifungal that is not licensed for use in children <13 years of age. Despite this and by necessity, it is used extensively in paediatric hospitals for prophylaxis of invasive fungal disease.

Objectives

To determine whether initial prophylactic dosing recommendations attain a posaconazole plasma concentration of ≥700 ng/mL in immunocompromised children <13 years of age.

Patients and methods

We performed 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 for ≥7 days and who had a posaconazole concentration measured after ≥7 days. Posaconazole plasma concentrations and rate of breakthrough infection were recorded.

Results

A total of 70 patients were included with a median age of 5 years (range 3 months to 12 years). The 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 ≥700ng/mL was 47.9%. Patients who were on a proton pump inhibitor, a histamine H₂ antagonist or metoclopramide, had mucositis or were enterally fed had a lower posaconazole plasma concentration compared with patients without these co-administered drugs/mucositis/enteral feeding (542.3 versus 1069.8 ng/mL; P<0.001). The breakthrough invasive fungal infection rate was 4.3% (3/70).

Conclusions

The studied 5 mg/kg posaconazole suspension every 8 h resulted in target concentrations in only 47.9% of patients and further studies looking at newer posaconazole formulations are needed.

Introduction

Invasive fungal infections (IFIs) are serious complications in immunocompromised paediatric patients that have had intensive chemotherapy or HSCT. The rate of IFI in this population has been reported to be high (25%) with significant mortality (40%–70%).^1–3 Antifungal prophylaxis in paediatric patients with haematological malignancies has been shown to reduce the incidence of IFI to 3%–5%.^2,4 Guidelines for antifungal prophylaxis in haematological malignancy and HSCT recommend posaconazole as an antifungal.^5,6 Unfortunately, posaconazole is not approved for use in children <13 years of age. There is increased off-label use of posaconazole in children <13 years of age despite limited safety, effectiveness and pharmacokinetic data.^4,7–9

Therefore, the primary aim of our study was to determine whether a posaconazole suspension dose of 5 mg/kg every 8 h is effective in achieving the target trough steady-state plasma concentration (≥700 ng/mL) for prophylaxis of IFI in immunocompromised children <13 years of age. We also aimed to investigate any correlations between posaconazole plasma concentrations and rate of breakthrough IFI.

Patients and methods

We conducted a retrospective, single-centre study at a large tertiary paediatric referral hospital where we analysed the medical records of paediatric patients prescribed posaconazole suspension from May 2013 to July 2017. Patients were eligible for inclusion when started on a posaconazole dose of 5 mg/kg every 8 h (maximum starting dose of 200 mg/dose). This dose was based on local policy and on a linear increase to the doses used in prior studies that used a lower target trough concentration.⁷ Therapeutic drug monitoring was conducted according to local policy and local guidelines.¹⁰

The inclusion criteria were: age <13 years; posaconazole indicated for primary/secondary prophylaxis of IFI; posaconazole administered for ≥7 days; and at least one trough plasma concentration (C_min) measured ≥7days after initiation of treatment.

Patient data were made available in electronic medical records, which contained medical histories, dosing information and pathology. Covariates that affect the absorption of posaconazole were also collected [e.g. proton pump inhibitors (PPIs), histamine H₂ antagonists (H₂As), metoclopramide, presence of mucositis and enteral feeding].^10,11

Assessment of posaconazole plasma concentrations

The primary endpoint of this study was the proportion of patients that achieved a C_min of ≥700 ng/mL after ≥7 days of treatment. This pharmacokinetic target was based on risk reduction for breakthrough fungal infection.^10,12 Posaconazole plasma concentration data were collected from a central referral laboratory (St Vincent’s Hospital, Sydney, Australia). This referral laboratory used a validated HPLC assay to measure posaconazole concentrations in blood; the assay has a linear range of 100–6000 ng/mL with accuracy and precision ranging from −2.0% to 5.5%.¹³

Assessment of efficacy

The European Organization for Research and Treatment of Cancer (EORTC) Cooperative Group’s definitions of proven, probable or possible IFI were used in this study.¹⁴ Effectiveness of prophylaxis was defined as the absence of breakthrough IFI. The observation period was while on posaconazole therapy until cessation or no greater than 100 days after HSCT/primary IFI/intensive chemotherapy. As standard practice, patients were monitored for clinical signs of infection, laboratory work-up and radiological investigations.

Statistical analysis

Descriptive statistics were used to describe the patient cohort initiation of posaconazole dosing. Patient outcomes (e.g. breakthrough IFI, development of mucositis, enteral feeding, PPI/H₂A use and posaconazole plasma concentrations) were described on a per-presentation basis.

A χ² or Fisher’s exact test was used to analyse the categorical variables associated with patients with steady-state posaconazole C_min of ≥700 ng/mL. This was the first level after steady-state was achieved and was defined as 7 days from initiation. A Wilcoxon signed-rank test was used to analyse mean posaconazole C_min where appropriate and logistic regression analysis was used to analyse patient and treatment factors associated with higher mean posaconazole C_min and the probability of breakthrough infection. IBM SPSS version 1.0.01012 was used for the analysis and P<0.05 was considered statistically significant.

Ethics

Ethics, waiver of patient consent and governance approval were obtained from the Sydney Children’s Hospitals Network (AU/1/132235).

Results

Patient characteristics

A total of 70 immunocompromised paediatric patients on posaconazole were included in our study (Table 1) and 92 posaconazole concentrations were recorded during the observation period. The median age was 5 years (range 3 months to 12 years) and 39 (55.7%) patients were 5 years or younger. Most patients in this study were diagnosed with ALL (32.9%) or AML (31.4%). One-fifth of patients were on a PPI and a quarter of patients were on metoclopramide. More than half (54.3%) of the patients in our study had at least one covariate that affected the absorption of posaconazole (e.g. being on a PPI, an H₂A or metoclopramide, having mucositis or were enterally fed). The mean duration of prophylaxis was 88 days (range 32–168  days).

Posaconazole plasma concentration

Target steady-state posaconazole C_min was reached in 47.9% of patients who were started on 5 mg/kg every 8 h orally. The mean posaconazole C_min was 783.4 ng/mL (IQR 428.3–980 ng/mL) (Table 2). Patients with one or more covariate that affected posaconazole absorption (e.g. on PPI/H₂A/metoclopramide, had mucositis or were enterally fed) were less likely to attain the target C_min (13.2% ≥1 covariate versus 90.6% no covariate; P<0.001) (Table 2) and had lower mean posaconazole C_min (542.3 ng/mL ≥1 covariate versus 1069.8 ng/mL no covariate; P<0.001). Each of the individual covariates was found to result in lower mean C_min and lower percentages of patients with target C_min (Table 2). We found that HSCT patients were less likely to attain a first measured steady-state C_min ≥700ng/mL and had lower C_min compared with non-HSCT patients [14.7% versus 85.3% (P=0.02) and 569.1 versus 863.3 ng/mL (P=0.02), respectively].

Effectiveness of IFI prophylaxis

Three of the 70 patients (4.3%) had a probable breakthrough IFI according to EORTC definitions. All three patients with breakthrough IFI had a C_min <700 ng/mL (365, 522 and 612 ng/mL). The mean C_min was significantly lower in the patients with breakthrough IFI compared with those who had had successful prophylaxis (599.6 versus 850.5 ng/mL; P=0.002). Lower posaconazole C_min values were correlated with a higher probability of breakthrough IFI based on logistic regression analysis (P=0.04; r² = 0.27).

Discussion

In this study, we observed that >50% of the patients <13 years of age did not achieve target first steady-state C_min (≥700 ng/mL) with an initial dosing regimen of 5 mg/kg every 8 h with the suspension formulation. We also observed that although the breakthrough IFI rate was low, those patients with IFI had a mean steady-state C_min <700 ng/mL. These results are important as they demonstrate the need for improved initial dosing with the posaconazole suspension to ensure that patients <13 years of age achieve target concentrations earlier and also sustain them.

Our study is the first, to our knowledge, to significantly show that covariates significantly affect the absorption of posaconazole suspension in children <13 years of age. We found that a starting dose of 5 mg/kg every 8 h (maximum dose of 200 mg/dose) was significantly more likely to achieve target C_min (90.6% versus 13.2%; P<0.001) and attain higher mean C_min (1069.8 versus 542.3 ng/mL; P<0.001) if the patients did not have mucositis, were not enterally fed or were not taking concurrent medications such as a PPI, an H₂A or metoclopramide. Each of these covariates led to a significantly lower mean posaconazole C_min and poor target concentration attainment (Table 2). This result supports empirically different dosing regimens for these patients or switching to the modified release tablet to overcome this problem. Although the median age of children in our study was 5 years, 45% of patients were able to swallow tablets in our study. During the study period, the modified release tablet had only just been released and there was no guidance on dosing in children. In a more recent study in children, posaconazole exposure was found to be substantially higher after the intake of modified release tablets compared with the suspension.¹⁵

Our study has some limitations related to the retrospective nature of the data collection. We were unable to collect data on other factors such as diarrhoea, vomiting and/or timing of drug administration in relation to food. These factors are known to affect total exposure of posaconazole in adults.¹⁶

A larger retrospective study (n=84) had similar findings, where doses of 10–12 mg/kg/day were given and around 63% achieved a similar target C_min (≥700 ng/mL) for prophylaxis. Fifteen percent were on PPIs, but the effect of absorption covariates described in our study was not measured. Similarly, low rates of breakthrough infection of 5% (4/84) were also found.¹⁷

Recently, a large, prospective, multicentre sequential dose escalation study (n=142) investigated posaconazole suspension doses ranging from 12 to 18 mg/kg/day, depending on age, and aimed for lower concentration targets (>500 ng/mL).¹⁸ Posaconazole concentrations were measured in the same number of patients as in our study (n=70) and, similarly, only 57% achieved concentrations >500 ng/mL. Interestingly, they found that increasing the dose from 12 to 18 mg/kg/day or increasing the frequency (e.g. from every 12 to 8 h) did not improve posaconazole exposure. Breakthrough IFIs were not described, but safety assessments found posaconazole suspension was well tolerated in children >3 months of age. The authors conclude there is a need to focus on new formulations (e.g. IV or oral granules) equivalent to the current adult modified release tablet.

In conclusion, the dosing regimen for posaconazole suspension for IFI prophylaxis used in this study consistently results in subtherapeutic concentrations. This is especially the case with patients with mucositis, with enteral feeding or on a PPI, an H₂A or metoclopramide. This indicates a need for further research of newer posaconazole formulations in immunocompromised children <13 years of age.

Funding

This study was carried out as part of our routine work.

Transparency declarations

T.L. has received financial support from MSD to attend a conference. Outside the submitted work, J.A.R. has consulted for Astellas, MSD, bioMérieux, Accelerate Diagnostics and Bayer, and has received investigator-initiated grants from MSD, Cardeas Pharma and The Medicines Company. J.-W.A. has received funding from MSD for investigator-initiated studies. Both other authors: none to declare.

References