Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction?

To determine whether the toxicity that occurs in some patients when lamotrigine (LTG) is added to carbamazepine (CBZ) is the result of either a pharmacokinetic or a pharmacodynamic interaction.

Escalating LTG doses were added to ongoing CBZ treatment in 47 patients. All patients had blood samples collected for drug concentration measurement, including the epoxide metabolite of CBZ, before starting LTG treatment and after stabilising at each dose escalation. Patients also were examined for signs of toxicity.

After LTG was introduced, nine patients demonstrated clinical signs of CNS toxicity, mainly diplopia and dizziness. There was no significant (p = 0.05) change in the serum concentrations of either CBZ or its epoxide metabolite when LTG was added either to the group as a whole or to the nine patients who experienced adverse CNS effects. LTG serum concentrations also were 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 concentrations were >8 mg/L on LTG introduction.

Toxicity is more likely to occur when LTG is added to CBZ if the initial CBZ level is high, typically >8 mg/L. This appears to be the result of a pharmacodynamic interaction. A reduction of CBZ dose usually resolves the toxicity, allowing the LTG dose to be escalated to maximal effect. It is not usually necessary to stop either drug.