Voriconazole Dosing in Children Younger Than 3 Years Undergoing Cancer Chemotherapy or Hematopoietic Stem Cell Transplantation

Yan, Shirley Qiong; Seyboth, Brian; Kobos, Rachel; Eaton, Anne; Seo, Susan K.; Cohen, Nina

doi:10.1093/jpids/pix022

Cited by 10 publications

(6 citation statements)

References 9 publications

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“…Independent of these considerations, however, a regimen consisting of 9 mg/kg intravenously TID for the first 3 days is clearly investigational, as it has been assessed by simulations only. For validation, a carefully designed clinical trial would be needed to validate exposure and safety, particularly in patients younger than 5 years of age, in whom accurate dosing is even more challenging (37).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children

Gastine

Lehrnbecher

Müller

et al. 2018

Antimicrob Agents Chemother

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The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [] = 51.5 mg/h/70 kg, central volume of distribution [] = 228 liters/70 kg, intercompartmental clearance [] = 21.9 liters/h/70 kg, peripheral volume of distribution [] = 1,430 liters/70 kg, bioavailability [] = 59.4%, = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h). Interindividual variabilities for ,, , and were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed clinical trial would be needed.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children

Gastine

Lehrnbecher

Müller

et al. 2018

Antimicrob Agents Chemother

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“…Low rates of therapeutic attainment are reported for children younger than 2 years using twice daily dosing. 17 Conversely, 3 times daily dosing achieved therapeutic concentrations in a case series of 3 patients aged 12 to 21 months. 18 Our findings further support that higher and more frequent (every 8 h) dosing regimens may be necessary for this age group.…”

Section: Discussionmentioning

confidence: 94%

Evaluation of Empiric Voriconazole Dosing and Therapeutic Drug Monitoring in Hospitalized Pediatric Patients

Schweiger,

Heiden,

MacBrayne

2024

Journal of Pediatric Hematology/Oncology

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Summary: Invasive fungal infections are a significant cause of morbidity and mortality in children with immunodeficiencies. Current dosing recommendations for voriconazole often result in subtherapeutic exposure in pediatric patients. In this single-center retrospective study, we reviewed hospitalized pediatric patients receiving voriconazole with at least one inpatient serum trough concentration measured. Patient characteristics and voriconazole dosing courses with associated trough concentrations were summarized for all patients as well as grouped by age (0 to 1 y, 2 to 11 y, and 12 to 18 y). Of 106 included patients, the median age was 9 years (range, 29 d to 18 y). Five hundred ninety courses of voriconazole were administered with 365 associated troughs. Most troughs were subtherapeutic (49%) and 30% of patients never attained a therapeutic trough. The median oral daily dose associated with a therapeutic trough was higher in younger age groups: 21.6 mg/kg 0 to 1 year, 17.9 mg/kg 2 to 11, and 9.5 mg/kg 12 to 18 years (P<0.001). Patients younger than 2 years had the largest proportion of subtherapeutic troughs and variability in dosing. Attainment of therapeutic voriconazole concentrations was challenging across all pediatric age groups. Higher starting doses for patients younger than 2 years are likely needed.

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“…9 In the pediatric literature, the use of mold-active prophylaxis, including current standards of voriconazole and posaconazole, results in low breakthrough IFD rates of 0% to 11% in oncology and patients with HCT, even without consideration for the variable exposure with these drugs. [10][11][12][13][14] The breakthrough rates are yet to be determined with the use of ISA prophylaxis. In the last several years, several centers have also implemented and evaluated the use of ISA for prophylaxis in the adult population.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Use and Efficacy of Isavuconazonium Sulfate in a Pediatric Oncology and Stem Cell Transplant Population: A Single Institution Retrospective Review

Kunvarjee,

Siver,

Mathew

et al. 2024

Journal of Pediatric Hematology/Oncology

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Isavuconazonium sulfate (ISA) is a triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis in adults. This single-center, retrospective review of pediatric oncology and stem cell transplant patients receiving ISA for prophylaxis (n=20) or treatment (n=6) of invasive fungal disease (IFD) aims to characterize real-world clinical efficacy and toxicity of ISA in patients <18 years of age. Of 20 patients receiving ISA for prophylaxis, three patients had presumed breakthrough IFD (1 proven, 2 probable/possible). No adverse effects were attributed to ISA use or led to the discontinuation of therapy.

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Voriconazole Dosing in Children Younger Than 3 Years Undergoing Cancer Chemotherapy or Hematopoietic Stem Cell Transplantation

Cited by 10 publications

References 9 publications

Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children

Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children

Evaluation of Empiric Voriconazole Dosing and Therapeutic Drug Monitoring in Hospitalized Pediatric Patients

Characterization of the Use and Efficacy of Isavuconazonium Sulfate in a Pediatric Oncology and Stem Cell Transplant Population: A Single Institution Retrospective Review

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