Abstracts

Zonisamide (ZNS) is a broad spectrum antiepileptic drug that exhibits a significant interaction with phenytoin (PHT): the half-life of ZNS is decreased by 60% (from 69 hours to 28 hours) due to the induction of enzymatic metabolic activity by PHT. Our objective was to explore this interaction with particular attention to the reverse drug interaction, i.e., the withdrawal of PHT therapy and its clinical implications for ZNS dosing. We developed a pharmacokinetic multiple-dosing model based upon a previously published multiple-dose clinical study of ZNS in normal volunteers. Using this model, we simulated the addition of PHT to ZNS monotherapy. We also simulated the withdrawal of PHT from binary therapy. In these simulations we assumed that enzyme induction due to PHT occurred over a 7 day period (i.e., the half-life of ZNS decreased gradually over a 7 day period). We also assumed that the de-induction of enzyme metabolic activity occurred over a 7 day period and that this de-induction phase did not occur until PHT levels were substantially zero, which we assumed occurred 7 days after the discontinuance of PHT therapy. The decline in ZNS plasma levels upon adding PHT was 60%; perhaps more significantly, the ZNS plasma levels seen on monotherapy were more than double those seen with PHT co-therapy. We note that in co-therapy with PHT, ZNS dosing levels could easily be pushed from 200 mg BID to as high as 400 mg BID and still have plasma levels in the therapeutic range of 15-30 mcg/ml. When withdrawing PHT from co-therapy, there is a 7 day period during which PHT levels are declining to zero and the enzymatic metabolic activity is still induced. De-induction occurs after PHT levels are virtually zero and we assume to occur over 7 days. In this case the ZNS dose must be decreased to a target level of 200 mg BID. Assuming that we raised the dose of ZNS to 400 mg BID when given with PHT, we recommend decreasing the ZNS dose beginning 7 days after discontinuing PHT therapy. Thereafter we recommend decreasing the ZNS dose to an intermediate level (300 mg BID in our example) for 3 days (6 doses) and then beginning the 200-mg-BID maintenance dose regimen. This strategy is based on solid pharmacokinetic evidence and maintains plasma levels of ZNS in the therapeutic range throughout the transition ZNS dosing when given with PHT can be rationally elevated from the monotherapy dose recommendation of 200 mg BID up to a 400 mg BID level. The adherence to a 200 mg BID dose in co-therapy with PHT may explain apparent failure to achieve additional antiepileptic activity when adding ZNS. The reverse drug interaction occurs when PHT is withdrawn from ZNS therapy. Because of the dramatic effect of PHT on ZNS half-life, dose adjustments are necessary when PHT is withdrawn. (Supported by Eisai, Inc.)