Voriconazole plasma concentrations and dosing in paediatric patients below 24 months of age
Silke E Gastine1, Kerstin K Rauwolf2, Stephanie Pieper2
1Institute of Pharmaceutical and Medical Chemistry - Department of Clinical Pharmacy, Westphalian Wilhelms University Münster, Münster, Germany.
Insights
Voriconazole (VCZ) dosing in children under 24 months is not well-established. This study found no increased toxicity but revealed mostly subtherapeutic exposures, highlighting the need for further pharmacokinetic research in this young population.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Infectious Diseases
Background:
- Voriconazole (VCZ) is a crucial antifungal medication approved for children aged 24 months and older.
- Limited data exists regarding VCZ dosing and exposure in infants under 24 months.
- This study addresses the scarcity of information on VCZ use in this vulnerable pediatric group.
Purpose of the Study:
- To evaluate the safety and efficacy of voriconazole (VCZ) in immunocompromised children younger than 24 months.
- To assess VCZ trough concentrations and tolerability in this age group.
- To identify potential correlations between VCZ dosage, exposure, and adverse events.
Main Methods:
- Retrospective analysis of 50 voriconazole treatment episodes in 17 children aged 3 to <24 months.
- VCZ administered for prophylaxis or empirical treatment, orally or intravenously.
- Trough concentrations and hepatic function parameters were monitored; adverse events were recorded.
Main Results:
- Most patients (57.9%) exhibited subtherapeutic VCZ trough concentrations (<1 mg/L).
- Only 34.2% of samples achieved the recommended target range (1-6 mg/L).
- No significant changes in hepatic function were observed, and only 6% of episodes were discontinued due to adverse events.
Conclusions:
- Voriconazole (VCZ) appears to have a favorable safety profile in children under 24 months.
- Current empirical dosing strategies often lead to subtherapeutic exposures in this age group.
- Further pharmacokinetic studies are essential to optimize VCZ dosing in infants and very young children.
Abstract:
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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