NONLINEAR MULTIPLE-DOSE PHARMACOKINETICS OF THE DOPAMINE REUPTAKE INHIBITOR VANOXERINE

The human pharmacokinetics of vanoxerine (GBR 12909) were studied in 1 4 normal subjects with a multiple-dose regimen. In a crossover design, each subject received daily oral doses of 25, 75, and 125 mg for 14 d ays at ear-h dose level with washout periods of 7 days duration. Drug concentrations in serum during and after dosing were estimated by an H PLC method sensitive to 2 nmol/L (corresponding to 1.04 ng/mL). Drug a ccumulation was observed during dosing at the two highest dose levels, but near steady-state conditions were attained within 9-11 days of do sing. Estimates of steady-state concentrations all showed statisticall y significant deviations from dose linearity in the form of disproport ionately higher concentrations at higher dose levels than expected fro m drug concentrations in serum at lower doses. The nonlinear pharmacok inetics was most likely due to increasing bioavailability with dose. T he mean elimination half-lives were 53.5 and 66.0 h at 75 and 125 mg/d ay, respectively, in accordance with the observed time to reach near s teady-state conditions. These estimates were higher than previous esti mates in less extensive studies.