Efficacy of a Standardized Premedication and Therapeutic Drug Monitoring Protocol for Pegaspargase to Prevent Hypersensitivity Reactions.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of a standardized premedication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. Pegaspargase is an essential therapeutic agent used for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. METHODS: This study was a retrospective cohort study conducted at Wolfson Children's Hospital, Jacksonville, Florida, and included pediatric ALL patients 0 to 21 years old. Patients were excluded if they had not received the appropriate premedication after protocol implementation or had received premedication before protocol implementation. Patients were separated into 2 groups: those who received premedication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. RESULTS: A total of 38 patients (50 doses in no premedication group; 80 doses in premedication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving premedication and TDM (5.3% vs 6.4%, p = 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. CONCLUSIONS: A standardized premedication protocol did not reduce the incidence of hypersensitivity reactions. Premedication to prevent hypersensitivity reactions may provide a potential drug cost savings. Further investigation is warranted to assess the efficacy of a standardized premedication and TDM protocol to prevent hypersensitivity reactions.

Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute Kidney Injury and Delayed Methotrexate Clearance in Pediatric Patients With Philadelphia Chromosome-positive B-Cell Acute Lymphoblastic Leukemia.

Imatinib, a tyrosine kinase inhibitor has improved survival in pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. There are no formal drug interactions listed between methotrexate and tyrosine kinase inhibitors. Four pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia had delayed methotrexate clearance during their first cycle of high-dose methotrexate while receiving imatinib, resulting in acute kidney injury. For subsequent high-dose methotrexate cycles, imatinib was withheld resulting in decreased acute kidney injury, shorter time to methotrexate clearance, less toxicity, and shorter hospitalizations. For pediatric patients with acute lymphoblastic leukemia receiving imatinib, we recommend escalated supportive care measures including increased hyperhydration and leucovoruin frequency. For patients with toxicities secondary to delayed clearance or need for glucarpidase, we recommend holding imatinib with subsequent high-dose methotrexate courses.

Comparison of Rapid Hydration and Standard Hydration Prior to Ifosfamide Administration in Pediatric Patients: A Safety and Efficacy Study.

OBJECTIVES: Adequate hydration status prior to chemotherapy initiation prevents nephrotoxicity in patients receiving potentially nephrotoxic regimens. The purpose of this study was to evaluate the time to initiation of ifosfamide administration between patients receiving standard 6-hour pre-hydration versus 1-hour rapid pre-hydration. METHODS: A retrospective study was conducted to determine the primary endpoint of time to ifosfamide administration. Patients 1 to 21 years of age who received ifosfamide with standard 6-hour pre-hydration (125 mL/m2/hr for 6 hours) between September 2017 and January 2018 or 1-hour rapid pre-hydration (750 mL/m2/hr for 1 hour) between September 2018 and March 2019 were included. Secondary endpoints included the incidence of hemorrhagic cystitis, incidence of acute kidney injury (AKI), urine specific gravity, amount of time that ifosfamide was delayed from the originally scheduled administration time, the number of times ifosfamide was delayed greater than 4 hours from the originally scheduled administration time, and length of stay. RESULTS: A total of 128 patients were included; 68 patients received standard 6-hour pre-hydration and 60 patients received 1-hour rapid pre-hydration prior to ifosfamide administration. Time to ifosfamide administration was reduced from an average of 9.3 hours to 2.4 hours (p < 0.0001). There was no incidence of hemorrhagic cystitis or AKI in either group. CONCLUSIONS: The 1-hour rapid pre-hydration protocol significantly reduced the time to ifosfamide administration without an increase in adverse effects.

Intravenous and Oral Posaconazole Pharmacokinetics in a Five-Year-Old With Mucor: A Case Report and Review of the Literature.

Posaconazole is a lipophilic triazole antifungal that exhibits variable absorption when administered orally. It possesses a broad spectrum of activity against various fungi, such as Aspergillus and traditionally resistant molds such as Rhizopus and Mucor, which carry a poor prognosis. Unfortunately, the tablet and suspension formulations of posaconazole are Food and Drug Administration approved for treatment of fungal diseases only in patients older than 13 years of age. Furthermore, the approval of the IV formulation is exclusively for adult patients. Nevertheless, the extended spectrum of activity and available dosage forms make it an attractive option for pediatric use. The data that exist to guide dosing of posaconazole in young pediatric patients are limited primarily to case series and case reports. Thus, we recommend therapeutic drug monitoring to ensure both safety and efficacy in pediatric patients. Herein we describe our experience with both oral and IV posaconazole in the salvage therapy of a 5-year-old female with extensive cutaneous Mucor. In contrast to previous reports, which show larger doses may be necessary to obtain therapeutic concentrations in pediatric patients as compared with adults, our patient reached targeted concentrations with weight-based dosing.

Posaconazole pharmacokinetics in a 2-year-old boy with rhino-cerebral-orbital zygomycosis.

Posaconazole is a triazole antifungal agent used as adjuvant or salvage therapy for the treatment of zygomycosis, an invasive fungal infection associated with high mortality. Oral posaconazole absorption is highly variable. We describe the pharmacokinetics of oral posaconazole in a 2-year-old boy with rhino-cerebral-orbital zygomycosis. Seven days after induction therapy for acute lymphoblastic leukemia, he was brought to the emergency department because of left eyelid swelling and was admitted to the hospital. Zygomycosis was diagnosed 12 days later. After we conducted a literature search and consulted with antifungal drug experts, a triple-antifungal regimen consisting of liposomal amphotericin B, caspofungin, and posaconazole was started. Given the severity of the disease, we aimed for posaconazole plasma trough concentrations greater than 1.25 µg/ml; the dosage necessary to achieve this goal was posaconazole 200 mg 4 times/day. After a difficult 105-day stay in the hospital and stabilization of the fungal infection, the patient was discharged. Caspofungin was discontinued at time of discharge, but the patient continued to receive amphotericin B lipid complex 7.5 mg/kg/day intravenously and posaconazole 200 mg orally 4 times/day. This is one of the few case reports describing posaconazole pharmacokinetics in a child younger than 8 years. In patients with extensive zygomycosis, a triple-antifungal regimen, combined with therapeutic drug monitoring of posaconazole, may be helpful.

High-dose magnesium sulfate infusion protocol for status asthmaticus: a safety and pharmacokinetics cohort study.

PURPOSE: To assess the safety and pharmacokinetics of high-dose magnesium sulfate (MgSO(4)) infusion in pediatric patients with status asthmaticus. METHODS: A prospective cohort study within a 20-bed pediatric intensive care unit in an academic community hospital. Patients 2-18 years of age admitted with status asthmaticus between 10/2009 and 8/2010 were included in the study. All patients received standard therapy for asthma, while the treatment group received an intravenous magnesium sulfate bolus of 50-75 mg/kg (0.2-0.3 mmol/kg) followed by 40 mg/kg/h (0.16 mmol/kg/h) for 4 h. Patients were monitored for cardiorespiratory complications. The treatment group underwent four blood draws to assess pharmacokinetic parameters. RESULTS: Nineteen patients were in the treatment group and 38 patients in the control group after exclusion criteria and consenting were completed. No clinically significant differences were found between groups. There were no interventions or discontinuations of MgSO(4) due to adverse events. In the treatment group, three patients had mild infusion-related reactions. Heart rate and respiratory rate were statistically significantly lower in the magnesium treatment group. CONCLUSIONS: The continuous infusions of MgSO(4) were safe at the studied doses and maintained serum magnesium (SrMg) and ionized magnesium levels similar to levels required to produce smooth muscle relaxation in other clinical settings. Further studies are needed to investigate the efficacy of high-dose continuous MgSO(4) infusion as an adjunctive treatment for severe asthma treatment and determine the SrMg level required to maintain airway smooth muscle relaxation.

Feasibility of short-term infusion of magnesium sulfate in pediatric patients with status asthmaticus.

OBJECTIVE: This report describes the feasibility of high-dose magnesium sulfate infusion in pediatric patients with status asthmaticus. METHODS: Retrospective chart review over a 3-year period of all patients younger than 18 years of age with status asthmaticus who underwent a high-dose magnesium sulfate infusion for 4 hours. All patients were breathing spontaneously but were refractory to conventional therapy. The magnesium sulfate infusion regimen was 50 mg/kg (for patients weighing >30 kg) or 75 mg/kg (for those weighing ≤30 kg) over a period of 30 to 45 minutes, followed by a continuous infusion of 40 mg/kg/hr for 4 hours. Information regarding vital and clinical respiratory signs, serum magnesium (SrMg), ionized magnesium (iMg), electrocardiograms, and cardiac troponin levels were retrieved. We analyzed the relationship between SrMg and iMg by using linear regression analysis. RESULTS: Nineteen patients were included. At the end of the infusion, SrMg levels were 4.4 ± 0.8 mg/dL, and iMg levels were 0.95 ± 0.2 mmol/L. SrMg levels only moderately predicted iMg (r(2) = 0.541). There were no reports of hypotension, respiratory failure, neurological problems, or nausea. Discomfort at the site of infusion was reported in three cases. Troponin levels (n = 12) and electrocardiograms (n = 12), when available, were noted at the end of the infusion and were normal in all patients p=0.01. CONCLUSIONS: In this case series, short-term high-dose administration of magnesium sulfate in the context of status asthmaticus was feasible, and we did not observe clinical complications with its use. Total SrMg was inadequate to reflect the active form of magnesium, iMg. The dose used achieved theoretical therapeutic levels of iMg.

Methemoglobinemia induced by rasburicase in a pediatric patient: a case report and literature review.

Rasburicase is a recombinant urate oxidase enzyme indicated for tumor lysis syndrome (TLS), a potential life-threatening oncologic emergency that occurs most commonly during chemotherapy for hematological malignancies. As a result of the defects in the physiological antioxidant pathway, erythrocytes of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are not protected against the oxidating stress exerted by hydrogen peroxide generated with the administration of rasburicase. Therefore, rasburicase is contraindicated in patients with known G6PD deficiency and the manufacturer recommends screening all patients with high risk for G6PD deficiency before initiating rasburicase therapy. However, it is logistically difficult in clinical settings because of the high risk of morbidity and mortality associated with TLS if treatment is delayed and the long turnaround time of the G6PD deficiency screening. Therefore, administering rasburicase to patients developing TLS before confirming a patient's G6PD status is practically inevitable. Methemoglobinemia, and/or hemolysis, may result from the oxidative stress. Descriptions of the clinical course should it happen are limited in the literature. There are eight reported cases of rasburicase-related methemoglobinemia, with or without hemolytic anemia, in the literature of which five are pediatric patients. Six reports (including three pediatric patients) had detailed descriptions of the event and management. The recent reports of methemoglobinemia observed in patients with probable G6PD activity further complicated the picture. We are reporting a 16-year-old patient diagnosed with Burkitt's lymphoma who developed methemoglobinemia after receiving one dose of rasburicase. He was managed by transfusion and oxygen support. The patient recovered well and the observed methemoglobinemia was reversible.