Dose optimisation of voriconazole with therapeutic drug monitoring in children: a single-centre experience in China

- Only 47.7% of children reached the therapeutic target at initial voriconazole dosing.
- Voriconazole exposure is significantly increased with omeprazole co-administration.
- A starting maintenance dose of 5-7 mg/kg is recommended for Asian children aged <2 years.

The pharmacokinetic profile of voriconazole is highly variable, rendering inconsistent and/or inadequate dosing, especially in children <2 years old. A retrospective analysis was performed in children receiving voriconazole with at least one plasma trough level (Ctrough) monitored. Statistical analyses were performed to examine the dose-exposure relationship as well as other factors potentially affecting voriconazole Ctrough in children of different ages. A total of 107 paediatric patients were included, of whom 75 were <2 years old. The voriconazole Ctrough was highly variable in patients aged <2 years and those aged 2-12 years. Only 47.7% of children reached the therapeutic target of 1.0-5.5 mg/L at initial dosing, whereas 48.6% of Ctrough values were subtherapeutic and 3.7% were supratherapeutic. The mean maintenance dose to reach an adequate Ctrough was 5.9 mg/kg compared with 5.1 mg/kg, resulting in insufficient levels (P = 0.005) in children aged <2 years. In this age group, the 5 to <7 mg/kg dose range significantly increased the chance of reaching the therapeutic target compared with the 3 to <5 mg/kg dose range (56.7% vs. 25.8%; P = 0.014). Overall, factors such as sex, age, liver function, renal function and co-administered medications explained only 15.9% of variability in voriconazole exposure. Co-administration of omeprazole significantly increased the voriconazole level (P = 0.032), likely through CYP2C19 inhibition. This is the largest series to date describing voriconazole dose-exposure relationships in children aged <2 years. A starting maintenance dose of 5 to <7 mg/kg intravenously twice daily may be required for most children of Asian origin to reach the therapeutic target.