Memantine pharmacotherapy: a naturalistic study using a population pharmacokinetic approach.

BACKGROUND AND OBJECTIVE Memantine plasma concentrations show considerable interindividual variability. High memantine plasma concentrations are associated with the occurrence of neuropsychiatric adverse effects such as confusion. The objective of the present study was, therefore, to investigate the reasons for the observed variability of the pharmacokinetics of memantine in a representative patient population and to explore patient covariates on drug disposition. SUBJECTS Fifty-six ambulatory Western European patients aged 50-91 years. METHODS This prospective study used a full population pharmacokinetic sampling design. After at least 11 days of continuous memantine intake, the patients provided pharmacokinetic profiles, with six measurements each over a 12-hour period, with a total of 335 serum memantine concentrations. Covariates considered for inclusion in the models were: subject demographic factors (age, total bodyweight, gender), laboratory tests (urinary pH), total daily dose of memantine, memantine formulation type, comedication eliminated via tubular secretion and smoking history. The model development was conducted in three sequential steps. First, an adequate basic structural model was chosen (e.g. a one-, two- or three-compartment pharmacokinetic model). The data were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed-effects model computer program NONMEM. Second, the effects of covariates were investigated on post hoc estimates using multivariate statistics. Third, the covariates with significant effects in the second step were used to build a final covariate pharmacokinetic model, again using NONMEM. RESULTS A two-compartment model with first-order absorption satisfactorily described memantine pharmacokinetics. In the final regression model, total bodyweight, memantine formulation type (solution vs tablets) and concomitant medication eliminated via tubular secretion were all important determinants of the apparent clearance (CL/F). The final regression model was: CL/F (L/h) = (1.92 + 0.048 x BW (kg)) x 0.530(FRM) x 0.769(CMD) where FRM = 1 for patients receiving memantine solution, otherwise FRM = 0; CMD = 1 for patients receiving a comedication eliminated via tubular secretion, otherwise CMD = 0; and BW is bodyweight. Compared with the basic model, the final population pharmacokinetic model explained 61% of the interindividual variance of the apparent clearance. CONCLUSIONS The population pharmacokinetic model that was developed identified a set of sources of variability in the apparent clearance of memantine, which can be used as a reference in order to optimise memantine therapy in Western European patients.