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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References
Birmaher B, Axelson D. Course and outcome of bipolar spectrum disorder in children and adolescents: a review of the existing literature. Dev Psychopathol. 2006;18:1023–35.
McClellan J, Kowatch R, Findling RL, Work Group on Quality I. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:107–25.
Vitiello B, Behar D, Malone R, Delaney MA, Ryan PJ, Simpson GM. Pharmacokinetics of lithium carbonate in children. J Clin Psychopharmacol. 1988;8:355–9.
Findling RL, Kafantaris V, Pavuluri M, McNamara NK, Frazier JA, Sikich L, et al. Post-acute effectiveness of lithium in pediatric bipolar I disorder. J Child Adolesc Psychopharmacol. 2013;23:80–90.
Findling RL, Kafantaris V, Pavuluri M, McNamara NK, McClellan J, Frazier JA, et al. Dosing strategies for lithium monotherapy in children and adolescents with bipolar I disorder. J Child Adolesc Psychopharmacol. 2011;21:195–205.
Findling RL, Landersdorfer CB, Kafantaris V, Pavuluri M, McNamara NK, McClellan J, et al. First-dose pharmacokinetics of lithium carbonate in children and adolescents. J Clin Psychopharmacol. 2010;30:404–10.
Findling RL, Frazier JA, Kafantaris V, Kowatch R, McClellan J, Pavuluri M, et al. The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation. Child Adolesc Psychiatry Ment Health. 2008;2:21.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.
Freeman AJ, Youngstrom EA, Michalak E, Siegel R, Meyers OI, Findling RL. Quality of life in pediatric bipolar disorder. Pediatrics. 2009;123:e446–52.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35.
Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions (CGI) scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 1997;73:159–71.
Busner J, Targum SD. The Clinical Global Impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4:28–37.
Bauer RJ. S-ADAPT/MCPEM user’s guide (Version 1.57). Software for pharmacokinetic, pharmacodynamic and population data analysis. Berkeley: Biomedical Simulations Resource (BMSR), University of Southern California (USC); 2010.
Bauer RJ, Guzy S, Ng C. A survey of population analysis methods and software for complex pharmacokinetic and pharmacodynamic models with examples. AAPS J. 2007;9:E60–83.
Bulitta JB, Bingolbali A, Shin BS, Landersdorfer CB. Development of a new pre- and post-processing tool (SADAPT-TRAN) for nonlinear mixed-effects modeling in S-ADAPT. AAPS J. 2011;13:201–11.
Bulitta JB, Landersdorfer CB. Performance and robustness of the Monte Carlo importance sampling algorithm using parallelized S-ADAPT for basic and complex mechanistic models. AAPS J. 2011;13:212–26.
Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28:481–504.
Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44:1051–65.
Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.
West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997;276:122–6.
McLeay SC, Morrish GA, Kirkpatrick CM, Green B. The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007. Clin Pharmacokinet. 2012;51:319–30.
Kleiber M. Body size and metabolism. Hilgardia. 1932;6:315–53.
Obach R, Borja J, Prunonosa J, Valles JM, Torrent J, Izquierdo I, et al. Lack of correlation between lithium pharmacokinetic parameters obtained from plasma and saliva. Ther Drug Monit. 1988;10:265–8.
Hunter R. Steady-state pharmacokinetics of lithium carbonate in healthy subjects. Br J Clin Pharmacol. 1988;25:375–80.
Gaillot J, Steimer JL, Mallet AJ, Thebault JJ, Bieder A. A priori lithium dosage regimen using population characteristics of pharmacokinetic parameters. J Pharmacokinet Biopharm. 1979;7:579–628.
Yang YY, Yeh EK, Chang SS, Deng HC, Lee CF. Maintenance lithium levels could be lowered: based on Taiwanese and Danish studies. J Formos Med Assoc. 1991;90:509–13.
Mason RW, McQueen EG, Keary PJ, James NM. Pharmacokinetics of lithium: elimination half-time, renal clearance and apparent volume of distribution in schizophrenia. Clin Pharmacokinet. 1978;3:241–6.
Lehmann W, Kanarkowski R, Matkowski K, Rybakowski J. Studies of lithium pharmacokinetics in patients with affective illness. Pol J Pharmacol Pharm. 1988;40:47–54.
Chen C, Veronese L, Yin Y. The effects of lamotrigine on the pharmacokinetics of lithium. Br J Clin Pharmacol. 2000;50:193–5.
Ku JS, Wu ZY, Fang YS, Pei YY. Clinical study on the pharmacokinetics of lithium carbonate. Int J Clin Pharmacol Ther Toxicol. 1987;25:648–50.
Turck D, Heinzel G, Luik G. Steady-state pharmacokinetics of lithium in healthy volunteers receiving concomitant meloxicam. Br J Clin Pharmacol. 2000;50:197–204.
Sysko R, Walsh BT. A systematic review of placebo response in studies of bipolar mania. J Clin Psychiatry. 2007;68:1213–7.
Hagino OR, Weller EB, Weller RA, Fristad MA. Comparison of lithium dosage methods for preschool- and early school-age children. J Am Acad Child Adolesc Psychiatry. 1998;37:60–5.
Weller EB, Weller RA, Fristad MA, Cantwell M, Tucker S. Saliva lithium monitoring in prepubertal children. J Am Acad Child Adolesc Psychiatry. 1987;26:173–5.
Geller B, Cooper TB, Sun K, Zimerman B, Frazier J, Williams M, et al. Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry. 1998;37:171–8.
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The authors thank the participants, their families and the site investigative teams for their invaluable contributions.
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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.
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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.
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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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DOI: https://doi.org/10.1007/s40262-016-0430-3