Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics
Department of Psychiatry
Medical Pharmacology | Mental and Social Health | Pediatrics | Psychiatry | Psychiatry and Psychology
BACKGROUND: Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients.
METHODS: Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations.
RESULTS: The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg LBW0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a > /=50 % reduction in YMRS in 74 % of patients, while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore, therapeutic drug monitoring will still be required even with these dosing strategies.
CONCLUSIONS: When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients.
DOI of Published Version
Clin Pharmacokinet. 2017 Jan;56(1):77-90. doi: 10.1007/s40262-016-0430-3. Link to article on publisher's site
Landersdorfer, Cornelia B.; Findling, Robert L.; Frazier, Jean A.; Kafantaris, Vivian; and Kirkpatrick, Carl M.J., "Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics" (2017). University of Massachusetts Medical School Faculty Publications. 1069.