Pharmacokinetic Modelling of Voriconazole to Develop an Alternative Dosing Regimen in Children [PublishAheadOfPrint]

Background. The pharmacokinetic variability of voriconazole in immunocompromised children is high and adequate exposure, particularly in the first days of therapy, is uncertain.

Methods. 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. Non-linear mixed effects modelling 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.

Results. A two compartment model with first order absorption, non-linear Michaelis-Menten elimination and allometric scaling best described the data (V_max= 51.5 mg/h/70 kg, V₁= 228 L/70 kg, Q= 21.9 L/h/70 kg, V₂= 1430 L/70 kg, F= 59.4%, K_m fixed to 1.15 mg/L, K_a fixed to 1.19 h^-1). Inter-individual variabilities were 63.6%, 45.4%, 67% and 1.34 on logit scale for V_max, V₁, Q and F, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/L (additive error). Monte Carlo simulations of a regimen of 9 mg/kg TID simulated for 24, 48 and 72 h followed by 8 mg/kg twice daily (BID) resulted in improved early target attainment relative to the currently recommended BID dosing regimen but no increased rate of accumulation thereafter.

Conclusions. Pharmacokinetic modelling 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 of 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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