Risk factors for subtherapeutic levels of posaconazole tablet

Abstract

Background

Posaconazole is the prophylactic antifungal of choice for patients with haematological malignancies at high risk of invasive fungal infections (IFIs). Studies have demonstrated that subtherapeutic concentrations of posaconazole are associated with breakthrough fungal infections and specific risk factors for subtherapeutic troughs associated with the suspension formulation have been identified. However, these risk factors have not been evaluated in a large patient population with the recently approved tablet formulation.

Objectives

To determine the risk factors for subtherapeutic posaconazole troughs associated with the tablet formulation in patients receiving posaconazole as IFI prophylaxis.

Patients and methods

From 1 February 2013 to 31 March 2015 all posaconazole serum trough concentrations were evaluated. A total of 157 patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and allogeneic stem cell transplant recipients with graft-versus-host disease were included for analysis.

Results

Overall, 28 patients (18%) had subtherapeutic troughs (<700 ng/mL). Patients were more likely to have subtherapeutic troughs if they had diarrhoea (n = 24; 83%) (P < 0.001), were receiving a proton pump inhibitor (n = 27; 93%) (P = 0.016) and weighed >90 kg (n = 14; 48%) (P = 0.047).

Conclusions

While the posaconazole tablet has provided more consistent therapeutic concentrations when compared with the suspension there may still be a role for therapeutic drug monitoring (TDM). These results may guide us to a specific population in which TDM is necessary to identify subtherapeutic troughs.

Introduction

Invasive fungal infections (IFIs) cause significant morbidity and mortality in immunocompromised patients.^1,2 Posaconazole is the prophylactic antifungal of choice in patients with AML or recipients of an allogeneic stem cell transplant (alloHCT).^3,4 Given the association between breakthrough IFIs and subtherapeutic posaconazole concentrations and the pharmacokinetic variability of posaconazole suspension, therapeutic drug monitoring (TDM) has become a valuable tool to potentially improve the efficacy of this agent.⁵ Although the ideal trough needed to prevent IFIs has not been established, studies suggest a trough <500–700 ng/mL to be associated with breakthrough IFIs during posaconazole prophylaxis.^6–9 In light of a lack of concentration-dependent toxicity and breakthrough IFIs at troughs of 500–700 ng/mL, troughs ≥700 ng/mL would be preferred.^6–9 Studies have reported risk factors associated with subtherapeutic levels of posaconazole suspension including gastrointestinal (GI) graft-versus-host disease (GVHD), mucositis, diarrhoea, poor nutritional intake and concomitant proton pump inhibitor (PPI) use.^{5–8,10–12} The recently approved delayed release tablet formulation of posaconazole was developed to overcome these effects. We conducted a retrospective case–control study to determine risk factors for subtherapeutic posaconazole troughs (<700 ng/mL) in patients with haematological malignancies and alloHCT recipients receiving the posaconazole tablet.

Patients and methods

Ethics

This study was approved by the Investigational Review Board (HUM00088819). Patient consent was not required given the retrospective nature of the study and drug levels were obtained as part of routine clinical practice.

Patients

This retrospective study was conducted at the University of Michigan Health System. All adult patients with a posaconazole level were identified through the electronic medical record. Patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and alloHCT recipients with GVHD were included. All patients received 300 mg of posaconazole once daily. Patients were excluded if they were <18 years of age, levels were obtained as an outpatient, they received the suspension formulation, troughs were drawn prior to steady-state (defined as <5 days after the start of the posaconazole), they were receiving posaconazole for IFI treatment, they received a non-FDA-labelled dosage or they missed any doses in the 5 days prior to measurement of the posaconazole level.

Methods

All posaconazole serum trough concentrations obtained from 1 February 2013 to 31 March 2015 were evaluated. Patient demographics, potential risk factors for subtherapeutic posaconazole troughs and clinical characteristics were obtained through retrospective chart review. Based on previous studies examining trough concentrations of the suspension formulation, the following risk factors were collected for evaluation: body weight, use of a PPI, presence of GI GVHD and presence of diarrhoea.^6,10–12 Posaconazole trough concentrations were measured using high-performance liquid chromatography assay–tandem mass spectrometry (Mayo Clinic Department of Laboratory Medicine and Pathology, Rochester, MN, USA). Cases with subtherapeutic troughs were compared with controls with therapeutic posaconazole trough concentrations. Subtherapeutic values were defined as <700 ng/mL. The primary endpoint was to determine risk factors associated with subtherapeutic posaconazole trough concentrations.

Statistical analysis

Continuous variables were compared using a two-tailed Student’s t-test. Non-normally distributed continuous variables were compared using a Mann–Whitney U-test. Dichotomous variables were compared using Fisher’s exact test. A backwards stepwise multivariable logistic regression analysis was conducted using likelihood ratios. Backwards logistic regression analysis was completed on all data points to evaluate variables associated with subtherapeutic posaconazole concentrations. Variables with a P value <0.1 on univariate analysis were included in the multivariable model and tested for interactions using backwards stepwise logistic regression. Variables with a P value <0.1 not included in the model due to collinearity were GI GVHD (covaries with diarrhoea). A receiver operating characteristic (ROC) curve was generated to assess the sensitivity and specificity of the model. A P value ≤0.05 was considered statistically significant and all P values were based on two-tailed tests. Statistical analyses were conducted using SPSS^® Statistics, version 22.0 (SPSS, Inc., Chicago, IL, USA).

Results

A total of 567 patients with a posaconazole level were identified. Of these, 157 had a posaconazole trough level that met inclusion criteria (Figure S1, available as Supplementary data at JAC Online). Patient demographics and disease characteristics are summarized in Table 1. Of the troughs included for evaluation, the overall median (range) was 1200 (110–5660) ng/mL. Overall, 18% (29/157) of patients had subtherapeutic troughs <700 ng/mL, with a median (range) of 469 (110–695) ng/mL. Conversely, 82% (128/157) had subtherapeutic troughs ≥700 ng/mL, with a median (range) of 1415 (719–5660) ng/mL.

The median (range) age of the cohort was 61 (18–89) and 62 (39%) were female. The most common indications for posaconazole prophylaxis were AML (n = 126; 80%) and GVHD post-alloHCT (n = 18; 11%). In patients receiving induction, the most common regimens were idarubicin/daunorubicin (7 + 3) (n = 47; 30%), FLAG (fludarabine, high-dose cytarabine and filgrastim) (n = 35; 22%) and clofarabine-containing regimens (n = 23; 15%).

Patients with troughs <700 ng/mL were significantly younger, with a median age of 60 versus 62 years (P = 0.028). Patients receiving posaconazole prophylaxis during treatment for GVHD were significantly more likely to have subtherapeutic troughs (n = 7; 39%) (P = 0.046). Alternatively, patients receiving posaconazole during AML induction chemotherapy were more likely to have troughs ≥700 ng/mL (n = 107; 85%) (P = 0.038). Patients who did not receive chemotherapy, primarily for GVHD, were more likely to have subtherapeutic troughs (n = 8; 38%) (P = 0.029). All other characteristics were similar between groups.

Potential risk factors for subtherapeutic trough concentrations were compared between groups (Table 2). Age, height, weight >90 kg, GI GVHD, PPI use and diarrhoea were found to result in significantly lower posaconazole troughs on univariate analysis. There were significantly more patients weighing >90 kg with subtherapeutic troughs (48% versus 28%) (P = 0.047). Patients receiving a PPI were more likely to have a trough of <700 ng/mL (93% versus 72%) (P = 0.016). Lastly, the presence of diarrhoea was associated with lower trough concentrations (83% versus 38%) (P < 0.001).

Using univariate results, a multivariable model with a high area under the ROC curve was created. AML, male gender, baseline albumin, receipt of a PPI and diarrhoea maintained significance in the multivariable model (Table 2). The area under the ROC curve of the model was high at 0.901 (95% CI 0.846–0.956).

Discussion

On multivariable analysis, we found diarrhoea, receipt of a PPI, male gender and low baseline albumin to be associated with subtherapeutic posaconazole troughs. A Phase I pharmacokinetic study found that 100% of patients had target troughs >700 ng/mL when receiving 400 mg of posaconazole twice daily.¹³ However, unlike the healthy volunteers in that study, patients receiving prophylaxis have multiple factors that may affect absorption, and dosing in clinical practice is significantly lower.

Patients with diarrhoea were more likely to have subtherapeutic troughs. This may be secondary to chemotherapy-induced GI toxicity, leading to decreased transit time and absorption. This has been previously reported in patients receiving the suspension with diarrhoea secondary to GI GVHD.⁵ Patients with GI GVHD were also more likely to have a trough <700 ng/mL (P = 0.088); however, our analysis found this to be collinear with diarrhoea.

Of patients with subtherapeutic troughs, 93% were on a PPI. A single-dose study found no significant difference with regards to posaconazole levels when co-administered with aluminum hydroxide/magnesium hydroxide, ranitidine, esomeprazole or metoclopramide; however, these were healthy volunteers and thus the findings may be less applicable to patients in clinical practice.¹⁴

Low albumin resulting in subtherapeutic troughs may be secondary to poor nutrition or increased GI protein losses due to diarrhoea, which may lead to decreased absorption. Male patients had significantly lower posaconazole troughs, potentially due to their increased weight and body habitus. Accordingly, patients weighing >90 kg had significantly lower troughs (878 ng/mL versus 1300 ng/mL) (P = 0.008).

Additional significant multivariable findings included patients undergoing treatment for AML. Patients with AML had a lower rate of subtherapeutic levels (15%) compared with the non-AML cohort (32%) and this finding carried through on multivariable analysis. This may be due to a higher rate of diarrhoea and the presence of GI GVHD in alloHCT patients.

There are several limitations to our analysis. We defined our steady state as 5 days in patients who received a loading dose based on the half-life of the drug and steady-state concentrations over time reported in the literature, while other authors define steady state as occurring after 6–8 days.^15,16 Additionally, due to the retrospective nature of the study, oral intake, amount of diarrhoea and incidence of mucositis could not be reliably assessed. Risk factors used for assessment were based upon available literature, but additional factors may exist that have not yet been identified. The small number of patients in each risk factor category may have limited our ability to demonstrate the significance of these factors in our analysis.

Based on the results of this study, the use of TDM with the tablet formulation should be taken under consideration. Prospective TDM of patients at risk for subtherapeutic levels or the use of preemptive dose adjustment in those with multiple risk factors for lower posaconazole trough concentrations should be explored in future analyses.

Funding

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

Transparency declarations

None to declare.

Supplementary data

Figure S1 is available as Supplementary data at JAC Online.

References

Author notes