Population pharmacokinetic modeling of sustained release lithium in the serum, erythrocytes and urine of patients with bipolar disorder

  • C. CouffignalEmail author
  • J. Bertrand
  • S. Sportiche
  • Marine Jarroir
  • S. El Balkhi
  • N. Djebrani-Oussedik
  • J. Poupon
  • X. Declèves
  • F. Mentré
  • F. Bellivier
Pharmacokinetics and Disposition



Lithium (Li), the first-line treatment of bipolar disorder, was first developed as an immediate-release form with a routine therapeutic drug monitoring 12 h after the last dose. In Europe, the most commonly prescribed form is a sustained release (srLi). Yet no pharmacokinetics (PK) study has been published of srLi, administered once a day, in adults. The present study describes srLi PK in the serum and erythrocytes of bipolar patients.


To assess srLi PK, we studied prospectively 17 French bipolar patients on a median dose of 1000 mg (600–1600) for at least 2 years. Serum (S), erythrocyte (E) concentrations, and urinary (U) amount were collected over 8 h after 15 days of morning intake using monitoring electronic medical system (MEMs). Population PK parameters were estimated using the SAEM algorithm (MONOLIX 4.3.3 software).


Using a population approach, we built a PK population model of srLi including one S compartment (VS = 23.0 L, ClS = 1.21 L h−1), one E compartment (VE = 64.7 L, ClSE = 3.63 L h−1, ClES = 9.46 L h−1), and one U compartment (F = 0.62) and estimate the ratio of concentrations to Li in E over S at 0.38 with 27% between-subject variability.


This is a PK model of srLi once a day in bipolar patients using a population approach simultaneously describing Li concentrations in serum, erythrocytes, and urine which provide an estimate of the ratio of concentration in erythrocyte over serum and its between-subject variability (BSV).


Lithium Pharmacokinetics Bipolar disorder Sustained release 



Part of the content of this work was presented at Population Approach Group of Europe Meeting, held in Budapest 2017.

Author contributions

Wrote manuscript: CC, JB, XD, FM, FB.

Designed research: FM, FB, SS, XD, CC.

Performed research: FB, SS, MJ.

Analyzed data: CC, FM, JB.

Contributed analytical tools: SE, JP, NDO.

Funding information

This study was supported by a grant from Ministry of research of France (PRES 2013).

Compliance with ethical standards

The study was conducted in accordance with good clinical practice and was approved by the ethics committee (IRB CPP IDF VI 2008-A01465-50). All patients or their legal representative signed an informed consent form for GAN and the ancillary pharmacokinetic study. Clinical Trial Registration of GAN study:; unique identifier: NCT02627404.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2018_2605_MOESM1_ESM.docx (1.8 mb)
ESM 1 (DOCX 1865 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • C. Couffignal
    • 1
    • 2
    • 3
    Email author return OK on get
  • J. Bertrand
    • 2
    • 3
  • S. Sportiche
    • 4
    • 5
    • 6
  • Marine Jarroir
    • 4
    • 5
    • 6
  • S. El Balkhi
    • 7
  • N. Djebrani-Oussedik
    • 8
  • J. Poupon
    • 8
  • X. Declèves
    • 6
    • 9
    • 10
  • F. Mentré
    • 1
    • 2
    • 3
  • F. Bellivier
    • 4
    • 5
    • 6
  1. 1.Département de BiostatistiqueAP-HP, HUPNVSParis Cedex 18France
  2. 2.UMR 1137Université Paris Diderot, IAMEParisFrance
  3. 3.UMR 1137INSERM, IAMEParisFrance
  4. 4.Département de Psychiatrie et de Médecine AddictologiqueAP-HP, HUSLS-LRB-FWDParisFrance
  5. 5.Université Paris DiderotParisFrance
  6. 6.UMR-S1144INSERMParisFrance
  7. 7.Service de Pharmacologie – Toxicologie et PharmacovigilanceCHU LimogesLimogesFrance
  8. 8.Département de Pharmacologie-toxicologieAP-HP, HUSLS-LRB-FWDParisFrance
  9. 9.Département Biologie du Médicament et ToxicologieAPHP, HUPCParisFrance
  10. 10.UMR-S1144Université Paris DescartesParisFrance

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