Abstracts

RATIONALE: Lamotrigine (LTG) is approved for monotherapy following withdrawal from enzyme-inducing AEDs. LTG is also frequently used in combination with valproate(VPA), and withdrawal to monotherapy in this setting is also frequently desirable. Given the known kinetic interaction between these 2 AEDs, clinically relevant questions that should be answered include 1) at what dose and/or concentration of VPA does this interaction begin, and 2) at what dose of VPA does maximal inhibition occur.
METHODS: LTG kinetic data was analyzed from 2 clinical studies. Study 1 was an open, randomized trial designed in part to evaluate LTG withdrawal to monotherapy in pts receiving VPA. LTG doses and serum concentrations were evaluated during each step-wise reduction in VPA dose. In Study 2, LTG kinetics were evaluated using single-dose LTG (25mg) given before and following [dsquote]low-dose[dsquote] VPA co-medication in healthy subjects. Serial blood samples were obtained over 120hrs in order to calculate LTG kinetic parameters including apparent oral clearance (Clo). Pharmacodynamic modeling (Emax)(ADAPT II v.4) was used to calculate EC90,50,25 values.
RESULTS: Study 1: LTG serum concentration data was evaluated in n=24 pts withdrawn to monotherapy. In this study, conversion to monotherapy was achieved using a fairly simple algorithm during which LTG plasma concentrations remained relatively stable. At higher initial doses of VPA (1000 mg/day or more), gradual VPA withdrawal resulted in slight increases in LTG concentrations, however at lower initial doses of VPA (500 mg/day or less), withdrawal of VPA led to meaningful decreases in LTG concentrations in all patients
Study 2: LTG Clo and VPA trough concentrations were determined in n=30 adult healthy female & male subjects. Mean trough VPA concentrations were 16.6[plusminus]14.4[mu]g/ml. Specifically, mean VPA concentrations at doses of 125,250,375 & 500mg/day were 6.5,13.9,16.1 & 31.9[mu]g/ml, respectively. Mean LTG Clo was reduced 35% (1.93[plusminus]0.61 vs 1.25[plusminus]0.46 l/hr, p[lt]0.05). EC90,50,25 values were 36.0[mu]g/ml, 4.2[mu]g/ml, and 1.4[mu]g/ml, respectively.
CONCLUSIONS: Taken together, these data suggest that VPA inhibition of LTG clearance begins at very low VPA doses & concentrations. Importantly, maximal inhibition (EC90, or 90% maximal inhibition) can be expected at VPA doses of approximately 500 mg/day, with the magnitude of inhibition diminishing at doses below this. These data may provide useful information to develop a dosing algorithm to convert patients to LTG monotherapy from.
Support: GlaxoSmithKline
Disclosure: Salary - GlaxoSmithKline; Grant - GlaxoSmithKline, Parke-Davis; Consulting - GlaxoSmithKline; Honoraria - GlaxoSmithKline,Pfizer,Abbott,UCB-Pharma