Characterization of Febrile Neutropenia Management in Children With Malignancies: A Single-Center Evaluation.

OBJECTIVE: Current recommendations for febrile neutropenia (FN) include initiation of broad-spectrum antibiotics without clear indications of when or how to de-escalate or target therapy, especially in those without microbiologically defined bloodstream infections (MD-BSIs). The purpose of this study is to characterize a pediatric FN population, FN management, and identify the proportion of patients with MD-BSI. METHODS: This study was a single-center, retrospective chart review of patients admitted to the University of North Carolina Children's Hospital between January 1, 2016, and December 31, 2019, with a diagnosis of FN. RESULTS: There were 81 unique encounters included in this study. MD-BSI was the etiology of fever in 8 FN episodes (9.9%). The most common empiric antibiotic regimen was cefepime (62%) followed by cefepime and vancomycin (25%). The most common de-escalation type was the discontinuation of vancomycin (83.3%), and the most common type of escalation was the addition of vancomycin (50%). The median antibiotic total duration in patients without MDI-BSI was 3 days (IQR, 5-9). CONCLUSIONS: In this single-center, retrospective review, most FN episodes were not due to an MD-BSI. There were inconsistencies in practice of when discontinuation of antibiotic therapy occurred in patients without MD-BSI. De-escalation or cessation of antibiotic therapy before neutropenia resolution did not result in any documented complication. These data suggest a role for implementing an institutional guideline to improve consistency in antimicrobial use in pediatric patients with febrile neutropenia.

Population Pharmacokinetics of Posaconazole in Immune-Compromised Children and Assessment of Target Attainment in Invasive Fungal Disease.

BACKGROUND AND OBJECTIVE: Posaconazole (PSZ) is a triazole antifungal for the management of invasive fungal disease (IFD) in adults and children. Although PSZ is available as an intravenous (IV) solution, oral suspension (OS) and delayed-release tablets (DRTs), OS is the preferred formulation for pediatric use because of potential safety concerns associated with an excipient in the IV formulation and difficulty in swallowing intact tablets by children. However, poor biopharmaceutical characteristics of the OS formulation leads to an unpredictable dose-exposure profile of PSZ in children, potentially risking therapeutic failure. The goal of this study was to characterize the population pharmacokinetics (PK) of PSZ in immunocompromised children and assess therapeutic target attainment. METHODS: Serum concentrations of PSZ were collected retrospectively from records of hospitalized patients. A population PK analysis was performed in a nonlinear mixed-effects modeling framework with NONMEM (v7.4). The PK parameters were scaled to body weight, then potential covariate effects were assessed. The final PK model was used to evaluate recommended dosing schemes through simulation of target attainment (as a percentage of the population having steady-state trough concentrations above the recommended target) using Simulx (v2021R1). RESULTS: Repeated measurement data of 202 serum concentrations of total PSZ were acquired from 47 immunocompromised patients between 1 and 21 years of age receiving PSZ either intravenously or orally, or both. A one-compartment PK model with first-order absorption and linear elimination best fit the data. The estimated absolute bioavailability (95% confidence interval) for suspension (Fs) was 16% (8-27%), which was significantly lower than the reported tablet bioavailability (Ft) [67%]. Fs was reduced by 62% and 75% upon concomitant administration with pantoprazole (PAN) and omeprazole (OME), respectively. Famotidine resulted in a reduction of Fs by only 22%. Both fixed dosing and weight-based adaptive dosing provided adequate target attainment when PAN or OME were not coadministered with the suspension. CONCLUSIONS: The results of this study revealed that both fixed and weight-based adaptive dosing schemes can be appropriate for target attainment across all PSZ formulations, including suspension. Additionally, covariate analysis suggests that concomitant proton pump inhibitors should be contraindicated during PSZ suspension dosing.

Evaluation of Posaconazole Dosing in Children and Young Adults: A Single-Center Review.

OBJECTIVE: Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations. METHODS: This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason. RESULTS: There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early. CONCLUSIONS: The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.

Impact of Adherence to Ibrutinib on Clinical Outcomes in Real-World Patients With Chronic Lymphocytic Leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with clonal expansion of small lymphocytes. Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a first-line treatment option, and recent data suggest that strict adherence is directly related to clinical outcomes. OBJECTIVES: The primary objective of this study was to quantify ibrutinib adherence rates in real-world patients with CLL on ibrutinib; secondary outcomes included progression-free survival and overall survival. METHODS: This retrospective study included subjects who were treated at a large academic medical center over approximately 5 years. Subjects were at least 18 years, diagnosed with CLL or small lymphocytic lymphoma, and treated with ibrutinib monotherapy for at least 6 months. Adherence was quantified using the medication possession ratio (MPR), which is the ratio of the sum of days' supply of medication in a period over the number of days in that period, and was based on fill history from the medical center's specialty pharmacy. RESULTS: For the 32 subjects in this study, the mean ibrutinib adherence rate was 91.7% (range, 84.4%-100%). Only 3 subjects had disease progression, and 1 death was recorded while on therapy (all with MPR < 95%); therefore, analyses of clinical outcomes were unable to be assessed due to a low number of events. There were no statistically significant differences in rates of adherence based on baseline characteristics and adverse drug events. CONCLUSION: In patients with CLL treated with ibrutinib, mean adherence was 91.7%, which is lower than rates seen in clinical trials.