title: Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, VIC, 3052, Australia. Cornelia.Landersdorfer@monash.edu.|Faculty of Pharmacy and Pharmaceutical Sciences, Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia. Cornelia.Landersdorfer@monash.edu.|Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA. Cornelia.Landersdorfer@monash.edu.
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.affiliation: Child and Adolescent Psychiatry, Johns Hopkins University, Baltimore, MD, USA.|Psychiatry, Kennedy Krieger Institute, Baltimore, MD, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Findling
authors.affiliation: Child and Adolescent Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jean A
authors.initials: JA
authors.lastname: Frazier
authors.affiliation: The Zucker Hillside Hospital, Glen Oaks, NY, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Kafantaris
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia.
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
mesh_terms: D000293:Adolescent; D018692:Antimanic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D001835:Body Weight; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D016651:Lithium Carbonate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009010:Monte Carlo Method
chemical_list: D018692:Antimanic Agents; D016651:Lithium Carbonate