A COMPARISON OF POPULATION AND STANDARD 2-STAGE PHARMACOKINETIC ANALYSES OF VIGABATRIN DATA

Vigabatrin (VGB), an irreversible inhibitor of GABA, is being develope d as an add-on therapy for uncontrolled complex partial seizure. A sin gle-dose study was conducted in three groups of subjects with normal, mild-to-moderate, and moderate-to-severe renal impairment to examine t he effect of renal function on the pharmacokinetics of VGB. Serial blo od samples were collected up to 60 h following a single 750 mg oral do se of VGB for the quantitation of drug concentrations. The plasma VGB concentration-time data were analyzed by mixed-effects modeling to est imate population pharmacokinetic parameters and to identify any signif icant demographic covariates. The parameters of VGB were also calculat ed by standard two-stage techniques and then compared to the results o btained using the mixed-effects analysis. Population VGB plasma concen tration-time profiles were best described by a two-compartment model w ith zero-order absorption. Creatinine clearance was observed to signif icantly affect the oral clearance of VGB (p < 0.05), i.e. a linear inc reasing relationship existed between the two variables. Other demograp hic factors had no influence on VGB pharmacokinetics. There were agree ments in the oral clearance, apparent volume of distribution during el imination, and half-life estimates calculated by both methods. In addi tion, the conventional technique identified a linear relationship betw een oral and creatinine clearances. In summary, mixed-effects modeling of serial vigabatrin data validated results determined by the standar d two-stage technique.