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

Eur J Clin Pharmacol. 2019 Apr;75(4):519-528. doi: 10.1007/s00228-018-2605-3. Epub 2018 Dec 15.


Purpose: 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.

Methods: 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).

Results: 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.

Conclusion: 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).

Keywords: Bipolar disorder; Lithium; Pharmacokinetics; Sustained release.

MeSH terms

  • Adult
  • Bipolar Disorder / blood*
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / urine*
  • Delayed-Action Preparations
  • Erythrocytes / metabolism*
  • Female
  • Humans
  • Lithium Carbonate / administration & dosage*
  • Lithium Carbonate / blood
  • Lithium Carbonate / pharmacokinetics*
  • Lithium Carbonate / urine
  • Male
  • Models, Biological*


  • Delayed-Action Preparations
  • Lithium Carbonate