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Population Pharmacokinetics and Exposure–Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms

  • Daichi Yamaguchi
  • Yasuhiro Tsuji
  • Miki Sonoda
  • Kenji Shin
  • Hiroko Kito
  • Chika Ogami
  • Hidefumi Kasai
  • Hideto To
  • Hidetoshi Kamimura
Original Research Article
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Abstract

Background and Objective

Lithium, which is used to treat bipolar disorder, has a narrow therapeutic blood concentration range and quickly reaches clinically toxic levels. We performed a population pharmacokinetic analysis with a lithium tubular reabsorption model including urinary pH and investigated the relationship between blood lithium concentration and tremor as a side effect.

Methods

Routine clinical data, including 389 serum concentrations, were collected from 214 patients orally administered an adjusted amount of lithium carbonate. Pharmacokinetics were described using a one-compartment distribution model with first-order absorption and elimination. The fractions of the MID (Li+ + LiCO3) and ION (2Li+ + CO32−) forms were calculated using the Henderson–Hasselbalch equation, and the influences of these fractions on clearance (CL) were evaluated. The rate of tremor development was analyzed using a logit model.

Results

Oral apparent CL (CL/F) was explained by nonrenal CL and renal CL, and renal CL was varied by the fractions of lithium forms influenced by urinary pH. The contribution of MID to CL was slightly larger than that of ION. The rate of tremor development was estimated to be more than 30% when the trough lithium concentration was greater than 1.26 mEq L−1.

Conclusion

Renal function and urinary pH are important indices in lithium treatment, so the serum concentration of lithium may be predicted based on the renal function and urinary pH.

Notes

Author Contributions

DY and YT contributed to the acquisition of data, analyzed and interpreted data, participated in the study design, and drafted the manuscript. CO analyzed and interpreted data and revised the manuscript. HK, HT, and HK contributed to the conception and design of the study and the interpretation of data. MS, SK, and HK contributed to serum concentration measurements and patient data sampling. All authors approved the final version to be published.

Compliance with Ethical Standards

Funding

This study was supported by a grant from SENSHIN Medical Research Foundation and Takeda Science Foundation.

Conflict of interest

The authors (Daichi Yamaguchi, Yasuhiro Tsuji, Miki Sonoda, Kenji Shin, Hiroko Kito, Chika Ogami, Hidefumi Kasai, Hideto To, and Hidetoshi Kamimura) declare no conflict of interest. All authors have completed the Unified Competing Interest form and declare that there was no support from any organization for the submitted work, no financial relationships with any organizations that may have an interest in the submitted work in the previous 3 years, and no other relationships or activities that may have influenced the submitted work.

Ethics approval

The present study was performed in accordance with the Helsinki Declaration after approval by the ethical review board of the University of Toyama (approval number: clinical 26-39). It was then approved by Yahata Kousei Hospital, Iizuka Hospital, and Fukuma Hospital.

Informed consent

Written consent was obtained from all patients, and patient privacy and personal information were respected.

References

  1. 1.
    Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349–52.PubMedGoogle Scholar
  2. 2.
    Schou M. Lithium in psychiatric therapy and prophylaxis. J Psychiatr Res. 1968;6:67–95.CrossRefPubMedGoogle Scholar
  3. 3.
    Grandjean EM, Aubry J-M. Lithium: updated human knowledge using an evidence-based approach. Part I: clinical efficacy in bipolar disorder. CNS Drugs. 2009;23:225–40.Google Scholar
  4. 4.
    Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381:1672–82.CrossRefPubMedGoogle Scholar
  5. 5.
    Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials. Bipolar Disord. 2007;9:551–60.CrossRefPubMedGoogle Scholar
  6. 6.
    Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36:375–89.CrossRefPubMedGoogle Scholar
  7. 7.
    Schou M. Pharmacology and toxicology of lithium. Annu Rev Pharmacol Toxicol. 1976;16:231–43.CrossRefPubMedGoogle Scholar
  8. 8.
    Thomsen K, Olesen OV. Precipitating factors and renal mechanisms in lithium intoxication. Gen Pharmacol. 1978;9:85–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Thomsen K. Renal handling of lithium at non-toxic and toxic serum lithium levels. A review. Dan Med Bull. 1978;25:106–15.PubMedGoogle Scholar
  10. 10.
    Kanba S, Kato T, Terao T, Yamada K. Guideline for treatment of bipolar disorder by the Japanese Society of Mood Disorders, 2012. Psychiatry Clin Neurosci. 2013;67:285–300.CrossRefPubMedGoogle Scholar
  11. 11.
    Schou M, Amdisen A, Trap-Jensen J. Lithium poisoning. Am J Psychiatr. 1968;125:520–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Prien RF, Caffey EM, Klett CJ. Relationship between serum lithium level and clinical response in acute mania treated with lithium. Br J Psychiatry. 1972;120:409–14.CrossRefPubMedGoogle Scholar
  13. 13.
    Gelenberg A, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med. 1989;321:1489–93.CrossRefPubMedGoogle Scholar
  14. 14.
    McKnight RF, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Watanabe S. Side effects of antimanic drugs. Jpn J Neuropsychopharmacol. 1989;11:49–58.Google Scholar
  16. 16.
    Ebid AIM, Abd-allah DAT, Elhabiby MMM. Pharmacokinetics of lithium in Egyptian bipolar patients: dosage adjustment approach. Pharmacol Pharm. 2014;5:425–32.Google Scholar
  17. 17.
    Henderson L. Concerning the relationship between the strength of acids and their capacity to preserve neutrality. Am J Physiol. 1908;21:173–9.Google Scholar
  18. 18.
    Hasselbalch K. Die Berechnung der Wasserstoffzahl des Blutes aus der freien und gebundenen Kohlensäure desselben, und die Sauerstoffbindung des Blutes als Funktion der Wasserstoffzahl. Biochem Z. 1917;78:112–44.Google Scholar
  19. 19.
    Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12:205–19.CrossRefGoogle Scholar
  20. 20.
    Anderson BJ, Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.CrossRefPubMedGoogle Scholar
  21. 21.
    Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102:2941–52.CrossRefPubMedGoogle Scholar
  22. 22.
    Anderson BJ, Holford NHG. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24:25–36.CrossRefPubMedGoogle Scholar
  23. 23.
    Cockcroft DW, Gault H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.CrossRefPubMedGoogle Scholar
  24. 24.
    Mould DR, et al. Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther. 2002;71:334–48.CrossRefPubMedGoogle Scholar
  25. 25.
    Matthews I, Kirkpatrick C, Holford N. Quantitative justification for target concentration intervention—parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides. Br J Clin Pharmacol. 2004;58:8–19.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Parke J, Holford NHG, Charles BG. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed. 1999;59:19–29.CrossRefPubMedGoogle Scholar
  27. 27.
    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13:143–51.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Thornhill DP. Pharmacokinetics of ordinary and sustained-release lithium carbonate in manic patients after acute dosage. Eur J Clin Pharmacol. 1978;14:267–71.CrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nielsen-Kudsk F, Amedisen A. Analysis of the pharmacokinetics of lithium in man. Eur J Clin Pharmacol. 1979;16:271–7.CrossRefGoogle Scholar
  31. 31.
    Yukawa E, Nomiyama N, Higuchi S, Aoyama T. Lithium population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens. Ther Drug Monit. 1993;15:75–82.CrossRefPubMedGoogle Scholar
  32. 32.
    Wing YK, Chan E, Chan K, Lee S, Shek CC. Lithium pharmacokinetics in Chinese manic-depressive patients. J Clin Psychopharmacol. 1997;17:179–84.Google Scholar
  33. 33.
    Findling RL, et al. First-dose pharmacokinetics of lithium carbonate in children and adolescents. J Clin Psychopharmacol. 2010;30:404–10.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Vesterqaard P, Poulstrup I, Schou M. Prospective studies on a lithium cohort. 3. Tremor, weight gain, diarrhea, psychological complaints. Acta Psychiatr Scand. 1988;78:434–41.Google Scholar
  35. 35.
    Feng Y, et al. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J Clin Pharmacol. 2014;78:106–17.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Daichi Yamaguchi
    • 1
  • Yasuhiro Tsuji
    • 1
  • Miki Sonoda
    • 2
  • Kenji Shin
    • 3
  • Hiroko Kito
    • 4
  • Chika Ogami
    • 1
  • Hidefumi Kasai
    • 1
  • Hideto To
    • 1
  • Hidetoshi Kamimura
    • 5
  1. 1.Department of Medical Pharmaceutics, Faculty of Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  2. 2.Department of PharmacyYahata Kousei HospitalKitakyushuJapan
  3. 3.Department of PharmacyIizuka HospitalIizukaJapan
  4. 4.Department of PharmacyFukuma HospitalFukutsuJapan
  5. 5.Department of PharmacyFukuoka University HospitalFukuokaJapan

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