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We describe our experience using the posaconazole 400-mg delayed-release tablet formulation once daily in 20 patients with hematologic malignancy or hematopoietic stem cell transplant who were unable to attain prespecified target minimum serum (trough) concentrations for treatment or prophylaxis of invasive fungal infection. The higher dose allowed the majority of patients to achieve prespecified target trough concentrations without incurring additional toxicities.
Posaconazole delayed-release tablet formulation (PTF) was developed to overcome the pharmacokinetic and administrative challenges associated with the oral suspension formulation (OSF) (1). Posaconazole has a role in preventing invasive fungal infections (IFIs) in patients with hematologic malignancy or hematopoietic stem cell transplant (HSCT) during neutropenia or while receiving certain immunosuppressive therapy (2). While PTF provides improved drug exposure compared to that of OSF, some patients are still unable to attain prespecified minimum serum (trough) concentrations of 0.7 μg/ml for IFI prophylaxis and 1.0 μg/ml for treatment (3). In this study, we examined 20 patients in whom the PTF dose was increased from the standard FDA-approved dosing (300 mg daily after a loading dose on day 1) to 400 mg daily because of a subtherapeutic trough concentration.
This was a retrospective single-center cohort study conducted at Oregon Health & Science University Hospital and Clinics (OHSU). The study was approved by OHSU's Institutional Review Board. The population comprised adult (age, ≥18 years) patients with hematologic malignancy or HSCT initiated on PTF at OHSU between April 2014 and February 2016. Eligible patients had a subtherapeutic posaconazole trough concentration while receiving PTF 300 mg daily and consequently received PTF 400 mg daily. Trough concentrations were obtained at least 5 days after initiation of therapy and the subsequent dose increase. Desired exposure concentrations were defined as ≥0.7 μg/ml for prophylaxis and ≥1.0 μg/ml for treatment (3). Data were extracted from the patients' inpatient and outpatient electronic medical records. Posaconazole quantitative serum concentrations were obtained with the high-performance liquid chromatography-tandem mass spectrometry assay (ARUP Laboratories, Salt Lake City, UT).
The primary outcomes were the median trough concentration and median change in trough concentration resulting from the dose increase from PTF 300 mg to 400 mg once daily. The rates of patients able to achieve target concentrations with the dose increase are also described. Secondary outcomes were the incidence of hepatotoxicity and change in corrected QT interval (QTc). Hepatic toxicities were defined as more than or equal to grade 2 increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin based on the Common Terminology Criteria for Adverse Events v4.03 (4). Baseline demographics, clinical characteristics, and outcomes were described with standard descriptive summary statistics. Statistical analyses were performed with Excel 2010 for Windows.
The baseline demographic characteristics of the patient cohort are described in Table 1. Therapy was frequently initiated and modified in the inpatient setting: 90% (18/20) for initiation of PTF 300 mg therapy and 70% (14/20) for the dose increase (400 mg). The median first trough concentration for the PTF 300-mg dose was 0.55 μg/ml (interquartile range [IQR], 0.40 to 0.60 μg/ml). After a dose increase to 400 mg daily, the median first trough concentration was 1.00 μg/ml (IQR, 0.78 to 1.20 μg/ml). The median change in trough concentrations from the 300- to the 400-mg dose increase was +0.55 μg/ml (IQR, 0.38 to 0.63 μg/ml). Individual trough concentrations for each patient on the 300- and 400-mg doses are shown in Fig. 1. Of the 18 patients receiving PTF for prophylaxis, 16 (88.89%) were able to achieve a trough concentration of ≥0.7 μg/ml after a dose increase to 400 mg daily. The remaining 2 patients were unable to attain the desired trough concentration and either were switched to voriconazole therapy or no longer required antifungal therapy. Of note, 1 of the 18 patients on prophylactic PTF had a presumed breakthrough infection (positive galactomannan assay) while receiving PTF 400 mg daily (trough, 1.8 μg/ml). The 2 patients receiving PTF for treatment achieved the target level (≥1.0 μg/ml) after a dose increase to 400 mg. The majority (60%) of the patient cohort had gastrointestinal (GI) dysfunction, including graft-versus-host disease and other inflammatory GI diseases.
Four patients (15%) experienced grade 1/2 elevation in AST/ALT, total bilirubin, or both during the course of the 400-mg therapy. All 4 patients had resolution of their laboratory abnormalities without discontinuation or dose deescalation. Electrocardiogram information was available for 7 patients pre- and post-dose increase (400 mg). None of the 7 patients experienced a QTc of >480 ms (range, 387 to 472 ms), and the mean change in QTc was +6.43 ms.
The development of PTF has greatly improved posaconazole exposures for patients who require antifungal prophylaxis or treatment (1). Our previous study revealed that ~9% of patients receiving PTF for prophylaxis in our center were unable to achieve the desired posaconazole trough concentration (5). Pharmacokinetic studies performed during the development of PTF suggest linear pharmacokinetics for this newer formulation (6, 7). However, no guidance exists regarding dose adjustments for patients deemed subtherapeutic for their respective indications. In an attempt to clarify this issue, we evaluated the impact of a 100-mg dose increase (300 to 400 mg daily) on the ability to achieve desired posaconazole trough concentrations (≥0.7 or ≥1.0 μg/ml for IFI prophylaxis or treatment, respectively). Though limited by a small sample size and one-arm design, our data suggest that increasing the dose of PTF from 300 to 400 mg daily is a reasonable intervention to achieve the desired minimum serum concentrations in patients unable to achieve the aforementioned target trough concentrations while receiving the 300-mg daily dosing. The 33% dose change (300 to 400 mg) resulted in a disproportionate 81.8% (0.55 to 1.00 μg/ml) increase in median trough concentration that may be explained by the compounded effect of “loading” the patient on 300 mg daily and then 400 mg daily in a single cohort; the other dose-escalation studies compared different doses in multiple cohorts (6, 7). The increased dose did not appear to incur additional hepatotoxicity or QTc prolongation.