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Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics

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Abstract

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.

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Acknowledgments

The authors thank the participants, their families and the site investigative teams for their invaluable contributions.

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Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, VIC, 3052, Australia

    Cornelia B. Landersdorfer

  2. Faculty of Pharmacy and Pharmaceutical Sciences, Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia

    Cornelia B. Landersdorfer & Carl M. J. Kirkpatrick

  3. Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Cornelia B. Landersdorfer

  4. Child and Adolescent Psychiatry, Johns Hopkins University, Baltimore, MD, USA

    Robert L. Findling

  5. Psychiatry, Kennedy Krieger Institute, Baltimore, MD, USA

    Robert L. Findling

  6. Child and Adolescent Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA

    Jean A. Frazier

  7. The Zucker Hillside Hospital, Glen Oaks, NY, USA

    Vivian Kafantaris

Authors
  1. Cornelia B. Landersdorfer
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  2. Robert L. Findling
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  3. Jean A. Frazier
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  5. Carl M. J. Kirkpatrick
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Corresponding author

Correspondence to Cornelia B. Landersdorfer.

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Funding

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (Contract No. HHSN275200503406C) and the Australian National Health and Medical Research Council (Career Development Fellowship number 1062509 to CBL).

Conflict of interest

Dr. Findling receives or has received research support, acted as a consultant and/or served on a Speaker’s Bureau for Alcobra, American Academy of Child and Adolescent Psychiatry, American Physician Institute, American Psychiatric Press, AstraZeneca, Bracket, Bristol-Myers Squibb, CogCubed, Cognition Group, Coronado Biosciences, Dana Foundation, Elsevier, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson and Johnson, Jubilant Clinsys, KemPharm, Lilly, Lundbeck, Merck, NIH, Neurim, Novartis, Noven, Otsuka, Oxford University Press, Pfizer, Physicians Postgraduate Press, Purdue, Rhodes Pharmaceuticals, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Transcept Pharmaceuticals, Validus and WebMD. Dr. Kirkpatrick has undertaken collaborative research projects unrelated to the current work with Roche and d3 Medicine. Dr. Kafantaris has received research support from AstraZeneca, the Brain and Behavior Foundation, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Pfizer and Sunovion. Dr. Frazier has received research support from Alcobra, Janssen, Neuren, Roche and SyneuRX International and has served on a data safety monitoring board for Forest Pharmaceuticals.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written assent was obtained from all participants included in the study and written informed consent was given by each participant’s guardian.

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Landersdorfer, C.B., Findling, R.L., Frazier, J.A. et al. Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics. Clin Pharmacokinet 56, 77–90 (2017). https://doi.org/10.1007/s40262-016-0430-3

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