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

Abstract

Lithium (Li), the first-line treatment of bipolar disorder, was first developed as an immediate-release form with a routine therapeutic drug monitoring 12h 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 1000mg (600-1600) for at least 2years. Serum (S), erythrocyte (E) concentrations, and urinary (U) amount were collected over 8h after 15days 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 = 23.0L, ClS = 1.21Lh-1), one E compartment (VE = 64.7L, ClSE = 3.63Lh-1, ClES = 9.46Lh-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).