Population modelling of lithium in paediatric patients with bipolar disorder: implications for dosing

Introduction. Bipolar I disorder (BP-I) leads to substantive psychosocial dysfunction. Lithium is well-established for treating BP-I in adults, however there is a paucity of information in paediatrics.

Aims. To characterise the pharmacokinetics/pharmacodynamics (PK/PD) of lithium in paediatrics and to predict lithium concentrations and clinical effects for novel dosage regimens.

Methods. Observed lithium concentrations and Young Mania Rating Scores (YMRS, a measure of the severity of manic episodes) over 24 weeks were available from a PK/PD study in 61 paediatric patients. All data were modelled simultaneously utilising S-ADAPT. Monte Carlo simulations were performed to predict concentrations and effects for different dosage regimens.

Results. Lithium PK was well characterised by a 2 compartment model with linear elimination. Including the effect of body weight on clearance and volume of distribution decreased the unexplained between subject variability (BSV). The population mean (BSV) clearance was 1.60 L/h/70kg0.75 (21%) and central volume of distribution was 23.5 L/70kg (15%). The average lithium concentration required for a 50% reduction in YMRS was 0.711 mEq/L (59%). A maintenance dose of 30 mg/kg/day lithium carbonate in 2 daily doses was predicted to achieve a 50% or greater reduction in YMRS in 75% of patients. At this dose 17% of patients would be expected to have morning trough concentrations above the nominal safety threshold of 1.4 mEq/L, therefore therapeutic drug monitoring will still be required.

Discussion. After accounting for body size, the PK parameters in paediatric patients were within the range of estimates reported for adults. PK/PD modelling supports development of the first evidence-based dosage regimens for safe and effective lithium treatment in paediatric patients.