Abstracts

LTG kinetics are altered by concomitant treatment with VPA. Therapeutic concentrations of VPA reduce LTG clearance by approximately 50%. Recent studies have suggested that metabolic inhibition of LTG by VPA is rapid in onset and potent. VPA concentrations of 5.6 [mu]g/ml are associated with 50% maximal inhibition of LTG clearance (EC50). An unresolved question involves the time-course of offset, or reversal of this interaction (de-inhibition). Our objective was to characterize changes in LTG serum concentrations immediatly following VPA discontinuation. Following written informed consent, 10 healthy adults (7 women/3 men) participated in this open label, 30 day study. At baseline, subjects received LTG (Lamictal 10 mg po q AM ) plus VPA (Depakote ER 500 mg po q AM) for 15 days. Blood was obtained on days 14 and 15 in order to determine steady-state serum concentrations of LTG and VPA. VPA was then abruptly discontinued, and serum concentrations of VPA and LTG were determined serially for an additional 15 days. Dosage of LTG was unaltered during this time. VPA and LTG serum concentrations were measured using established immunofluorometric and gas chromatographic methods, respectively. Statistical analysis included ANOVA Data was analyzed for 9 subjects, (1 subject excluded due to protocol violations). Following concurrent administration for 15 days, mean steady state serum concentrations of LTG and VPA were 457 ng/ml and 43.5 [mu]g/ml, respectively. The first day (study day 16) following VPA discontinuation, mean VPA concentration declined to 11.2 [mu]g/ml, while LTG remained unchanged (451.6 ng/ml). Three days following discontinuation (study day 18), VPA concentration was 0.9 [mu]g/ml. LTG concentrations had only modestly declined to 403.2 ng/ml (p=NS) Between study days 20-24, LTG concentrations progressively declined, and appeared to reach a new plateau by study days 26-28 (226.4 - 228.7ng/ml, p[lt]0.05 vs baseline), representing approximately a 50% decline in LTG concentrations as compared to baseline during concurrent administration. These observations demonstrate that the pharmacokinetic interaction between LTG and VPA is reversible. Within 3 days following the discontinuation of VPA, LTG concentrations begin to decline. Consistent with previous observations, VPA mediated inhibition appears, even at realtively low serum concentrations. By 7-9 days following the complete disappearance of VPA from serum, LTG concentrations appear to plateau. From a practical perspective, one would therefore expect LTG concentrations to decline by approximately 50% within 2 weeks following VPA discontinuation, unless dosage adjustments of LTG are made. These observations may be important in patients who are being converted from VPA + LTG combination therapy to LTG monotherapy. (Supported by GSK Research [amp] Development)