Sh. Ingwersen et al., NONLINEAR MULTIPLE-DOSE PHARMACOKINETICS OF THE DOPAMINE REUPTAKE INHIBITOR VANOXERINE, Journal of pharmaceutical sciences, 82(11), 1993, pp. 1164-1166
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.