CARBAMAZEPINE TOXICITY WITH LAMOTRIGINE - PHARMACOKINETIC OR PHARMACODYNAMIC INTERACTION

Purpose: To determine whether the toxicity that occurs in some patient s when lamotrigine (LTG) is added to carbamazepine (CBZ) is the result of either a pharmacokinetic or a pharmacodynamic interaction. Methods : Escalating LTG doses were added to ongoing CBZ treatment in 47 patie nts. All patients had blood samples collected for drug concentration m easurement, including the epoxide metabolite of CBZ, before starting L TG treatment and after stabilising at each dose escalation. Patients a lso were examined for signs of toxicity. Results: After LTG was introd uced, nine patients demonstrated clinical signs of CNS toxicity, mainl y diplopia and dizziness. There was no significant (p = 0.05) change i n the serum concentrations of either CBZ or its epoxide metabolite whe n LTG was added either to the group as a whole or to the nine patients who experienced adverse CNS effects. LTG serum concentrations also we re below the level at which the common signs of LTG toxicity, such as nausea, vomiting, or unsteadiness, are more likely to occur. In seven of the nine patients who exhibited CNS toxicity, CBZ serum concentrati ons were >8 mg/L on LTG introduction. Conclusions: Toxicity is more li kely to occur when LTG is added to CBZ if the initial CBZ level is hig h, typically >8 mg/L. This appears to be the result of a pharmacodynam ic interaction, ii reduction of CBZ dose usually resolves the toxicity , allowing the LTG dose to be escalated to maximal effect. It is not u sually necessary to stop either drug.