Abstracts

Rationale: Co-administration of lamotrigine(LTG)and valproate(VPA) is effective in refractory epilepsy.Pharmacokinetic interaction is characterized by the inhibitory effect of VPA on LTG glucuronidation,with reduction of its clearance,increasing plasma level at steady-state(SS) and half-life(t1/2).In adults,there was no correlation between the clearance of LTG,its doses and SS.In addition,efficacy was not related to LTG level.The rationale for this study is to determine pharmacokinetic interaction of VPA-LTG in children. Methods: We studied 51 children(<16 y;mean 8y)with refractory epilepsy,using VPA.Patients received LTG as add-on therapy. In the first 2 weeks, 0.1-0.15mg/kg of LTG was introduced added to VPA.In weeks 3-4, 0.1mg/Kg/day of LTG were added.Introduction consisted of a 10-12 weekly dose escalation and a blood sample was collected.After that, VPA was reduced by 50%.The maintenance mean dose of LTG was 1.2mg/kg/day (0.4-3mg/kg/day).Interviews were performed weekly to assess seizure control and adverse effects.Treatment was considered effective when >50% of seizure reduction was achieved.LTG and VPA plasma levels were measured by HPLC and FPIA,respectively.A serial assessment was performed in three patients admitted to the hospital for 12h,and blood was collected (30,60,90 and 120min)after LTG administration. Results: Co-administration was effective in 81.3%,with >75% seizure frequency decrease in 70.8%.Rash occurred in 3 patients. LTG was dose-linear,reaching a peak at 2.5h with a t1/2 of 21h,when administered in 5 controls(VPA monotherapy).The co-administration VPA-LTG raised t1/2 of LTG in 44h and decreased its clearance in 22%(from 1480 to 1158mL/h).This increase of t1/2 was dose-related. VPA led to an increase in the plasma concentrations of LTG(from 1.6µg/mL to 2.5µg/mL).Analysis with linear regression demonstrated correlation between plasma level of LTG and occurrence of adverse-effects (p<0.01).Patients with adverse-effects had concentrations of 4.5+/-2.7µg/mL(1.45-9.40µg/mL).Patients with rash increased LTG plasma levels 7.9+/-1.5µg/mL(6.3-9.4µg/mL) compared to others(2.2+/-0.8µg/mL) (p<0.05).This level was two times higher than the therapeutic range upper limit(1-4µg/mL) in adults.There was a correlation(linear regression) between mean concentrations of LTG and efficacy(p=0.019).Patients with seizure control >