Pharmacokinetics, Safety and Efficacy of Voriconazole in Pediatric Patients: An Update

Dokos, Charalampos; Pieper, Stephanie; Lehrnbecher, Thomas; Groll, Andreas H.

doi:10.1007/s12281-012-0090-1

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…The pharmacokinetics of voriconazole are complex and involve oxidative metabolization through several CYP450 isoenzymes with genetic polymorphisms in its major metabolic pathway, resulting in nonlinear pharmacokinetics and unpredictable doseexposure relationships that are further influenced by drug-drug interactions, inflammation, and variable oral bioavailability, particularly in children (17,(30)(31)(32). On the basis of the significant correlations between exposure and effect and the significant effects of TDM on treatment responses and adverse effects, TDM is advocated for children and adults in current management guidelines (16)(17)(18)(19)(20)33).…”

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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“…A high inter‐ and intraindividual variability with absence of a consistent correlation between dose and exposure in this age group has been previously reported for this age group, 10,27,28 and several studies have concluded that infants generally need higher doses than children 2–6 and 6–12 years of age 10–12,27,29–32 . The disposition of VCZ involves age‐dependent, saturable oxidative hepatic metabolization through CYP2C19, CYP3A4 and, to a lesser extent, CYP2C9, resulting in non‐linear PKs and unpredictable dose–exposure relationships 8,24 . The compounds disposition in children is further influenced by highly variable genetic polymorphisms in CYP2C19, relevant drug–drug interactions particularly via CYP3A4 and CYP2C19, inflammation and variable oral bioavailability through an intestinal first‐pass metabolism and food effects 8,15,24,33–38 .…”

Section: Discussionmentioning

confidence: 82%

“…2,[21][22][23] The recommended dosages with several revisions in the recommended dosages over time. 24,25 Currently, an intravenous dose of VCZ of 8 mg/kg BID (Day 1, 9 mg/ kg BID) and an oral dose of the suspension of 9 mg/kg BID have been adopted by both EMA and FDA for children ≥2 to 11 years of age and those 12 to 14 years of age weighing <50 kg. 6,7 The compound has not been systematically studied for regulatory approval in neonates and children <2 years due to the formerly prevailing perception of an only sporadic occurrence of invasive aspergillosis in this age group and concerns of more than functional ophthalmological adverse effects 26 and thus, dosing in this age group has remained empirical and based on the clinical judgement of the treating physician.…”

Section: Discussionmentioning

confidence: 99%

“…10-12, 27, 29-32 The disposition of VCZ involves age-dependent, saturable oxidative hepatic metabolization through CYP2C19, CYP3A4 and, to a lesser extent, CYP2C9, resulting in non-linear PKs and unpredictable dose-exposure relationships. 8,24 The compounds disposition in children is further influenced by highly variable genetic polymorphisms in CYP2C19, relevant drug-drug interactions particularly via CYP3A4 and CYP2C19, inflammation and variable oral bioavailability through an intestinal first-pass metabolism and food effects. 8,15,24,[33][34][35][36][37][38] Indeed, in larger population PK analyses 31,32,39 and in a physiologically based pharmacokinetic model 40 including children <24 months of age, the CYP2C19 phenotype and age were consistently found as the significant covariates.…”

Section: Discussionmentioning

confidence: 99%

“…The recommended dosages for adolescents ≥12 years correspond to the adult dosages and are 4 mg/kg of body weight two times daily (BID; Day 1, 6 mg/kg BID) for intravenous, and 200 mg BID (Day 1, 400 mg BID) for oral dosing 6,7 . Dose finding in children ≥2 to 11 years has been difficult with several revisions in the recommended dosages over time 24,25 . Currently, an intravenous dose of VCZ of 8 mg/kg BID (Day 1, 9 mg/kg BID) and an oral dose of the suspension of 9 mg/kg BID have been adopted by both EMA and FDA for children ≥2 to 11 years of age and those 12 to 14 years of age weighing <50 kg 6,7 .…”

Section: Discussionmentioning

confidence: 99%

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Voriconazole plasma concentrations and dosing in paediatric patients below 24 months of age

Gastine

Rauwolf

Pieper

et al. 2023

Mycoses

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Voriconazole (VCZ) is an important first‐line option for management of invasive fungal diseases and approved in paediatric patients ≥24 months at distinct dosing schedules that consider different developmental stages. Information on dosing and exposures in children <24 months of age is scarce. Here we report our experience in children <24 months who received VCZ due to the lack of alternative treatment options. This retrospective analysis includes 50 distinct treatment episodes in 17 immunocompromised children aged between 3 and <24 months, who received VCZ between 2004 and 2022 as prophylaxis (14 patients; 47 episodes) or as empirical treatment (3 patients; 3 episodes) by mouth (46 episodes) or intravenously (4 episodes) based on contraindications, intolerance or lack of alternative options. Trough concentrations were measured as clinically indicated, and tolerability was assessed based on hepatic function parameters and discontinuations due to adverse events (AEs). VCZ was administered for a median duration of 10 days (range: 1–138). Intravenous doses ranged from 4.9 to 7.0 mg/kg (median: 6.5) twice daily, and oral doses from 3.8 to 29 mg/kg (median: 9.5) twice daily, respectively. The median trough concentration was 0.63 mg/L (range: 0.01–16.2; 38 samples). Only 34.2% of samples were in the recommended target range of 1–6 mg/L; 57.9% had lower and 7.9% higher trough concentrations. Hepatic function parameters analysed at baseline, during treatment and at end of treatment did not show significant changes during VCZ treatment. There was no correlation between dose and exposure or hepatic function parameters. In three episodes, VCZ was discontinued due to an AE (6%; three patients). In conclusion, this retrospective analysis reveals no signal for increased toxicity in paediatric patients <24 months of age. Empirical dosing resulted in mostly subtherapeutic exposures which emphasises the need for more systematic study of the pharmacokinetics of VCZ in this age group.

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Antifungal Drugs

Bustamante¹,

Hidalgo²,

Campos³

2017

Current Progress in Medical Mycology

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Pharmacokinetics, Safety and Efficacy of Voriconazole in Pediatric Patients: An Update

Cited by 6 publications

References 29 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

Voriconazole plasma concentrations and dosing in paediatric patients below 24 months of age

Antifungal Drugs

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