NONPARAMETRIC-ESTIMATION OF POPULATION CHARACTERISTICS OF THE KINETICS OF LITHIUM FROM OBSERVATIONAL AND EXPERIMENTAL-DATA - INDIVIDUALIZATION OF CHRONIC DOSING REGIMEN USING A NEW BAYESIAN-APPROACH

A population analysis of the kinetics of lithium was performed from ex perimental and observational data in 113 subjects in order to propose a new approach for lithium dosage individualization. The kinetics of l ithium is described by a two-compartment model. Age, body weight, heig ht, and serum creatinine are included as covariates. Population analys is was performed by the nonparametric maximum likelihood method, which provides an estimate of the distribution of the five kinetic paramete rs and covariates. Mean lithium clearance was 1.50 L/h with a coeffici ent of variation (CV) of 38%, and was found to increase with body weig ht. Results were consistent with those of earlier studies and confirm a large interindividual variability. Data from a separate group of 35 patients were used to validate results: the estimated a priori and on covariate conditional distributions of the measured 24-h serum lithium concentration following a single dose were consistent with the corres ponding measurements. A Bayesian approach for individualizing dosing s chemes is proposed. This approach is based on minimization of a risk f unction expressing the deviation of the trough concentration at steady -state from the therapeutic range.