Introduction. Aciclovir is an antiviral widely used to treat herpes simplex virus (HSV) infections, including neonatal HSV encephalitis, where adequate serum and cerebrospinal fluid (CSF) exposure is needed. However, a paediatric population pharmacokinetic (PopPK) model characterising CSF penetration remains absent.
Aims. To develop a joint serum–CSF PopPK model in children aged 0–18 years to optimise aciclovir dosing.
Methods. In this five-year study, children aged 0–18 years receiving oral or 1-hour intravenous aciclovir were included. Opportunistic serum and CSF concentrations were analysed using NONMEM with a prior incorporating weight-based allometric scaling, serum creatinine influenced renal function and postmenstrual age maturation. Albumin, sex and white cell count were evaluated as covariates. Monte Carlo simulations evaluated ≥90% probability of target attainment (PTA) for 50%fT>IC₅₀ in serum and 100%fT>IC₅₀ in CSF (IC₅₀ 0.56 mg/L, HSV) with standard TID dosing and 24-hour continuous infusion (20–45 mg/kg/day) across three age groups (<4 months, 4 months–11 years, 12–18 years).
Results. A total of 147 children (range 0-17 years) contributed 254 observations (44% serum, 52% CSF, 4% both). A joint oral/IV one-compartment model with first-order absorption and elimination, linked to a CSF compartment, best described the data; albumin significantly influenced CSF influx rate constant. Oral bioavailability was 14.2% and CSF penetration was 35%. Standard TID dosing (20 mg/kg for <4 months, 15 mg/kg for 4 months–11 years, 10 mg/kg for 12–18 years) achieved ≥90% PTA across ages, except for CSF in children 4 months–11 years (82.3%). The proposed CI dosing achieved ≥90% PTA with 30 mg/kg/day in <4 months and 12–18 years, and 45 mg/kg/day in 4 months–11 years. Toxicity threshold exceedance (>25 mg/L) was rare (≤1.1%) and absent in older children.
Discussion. The developed PopPK model well characterised PK of aciclovir in both serum and CSF. Model simulation demonstrated that 24-hour continuous infusion achieves PK/PD exposure targets at lower total daily doses.