Abstracts

Traditional dogma is to increase drug dose to either complete seizure control or to clinical toxicity. Problems with this approach include difficulty in recognizing the onset of clinical toxicity and the inordinate time required to follow this procedure with multiple drug choices. A meta-analysis of published dose-response data suggests a decision on efficacy can often be made short of the point of clinical toxicity. For a particular drug, this possibility depends upon the shape of the dose-response curve. The dose above which a predefined incremental chance of clinically useful seizure reduction is unlikely may be defined as the [quot]decision point dose[quot]. At this point, it may be more rational to switch drugs rather than persist to higher doses. This point is best definable for drugs which display a ceiling effect, for which the dose-response curve flattens out. If the percentage of patients expected to respond to a clinically-useful degree to any dose higher than this is lower than the expected response rate to a differerent drug, weighing patient-specific factors, then the better choice may be switching drugs. The [quot]decision point dose[quot] was defined operationally as the dose beyond which an incremental increase in the responder rate, RR (patients with 50% improvement in seizure frequency from baseline) of more than 10% did not occur with cumulative higher doses, on average, in published dose-ranging trials, both controlled and open-label. Data for three representative drugs used as adjunctive treatment for partial-onset seizures were analyzed. Topiramate doses of 400mg/day produce an RR of about 40%; higher doses raise this [lt]5%. One trial reporting an RR for 450mg/day of 50.6% did not include a comparison to lower doses. For gabapentin, doses over 2400mg/day netted few additional responders, although doses in many studies did not exceed 1800mg/day. On the other hand, oxcarbazepine displayed a relatively linear dose-response relationship all the way through the top dose systematically tested, 2400mg/day. Dosing strategy should vary by drug. For oxcarbazepine, it makes sense to follow the traditional strategy of gradual dose increases to the point of clinical toxicity, since there is significant incremental benefit even at a dose, 2400mg, resulting in 67% dropouts from adverse events. Increases above the decision point doses for gabapentin, 2400mg, and topiramate, 400-450mg, for patients who have not yet responded, are unlikely to provide significant benefit for most patients, but will increase expense and delay other treatments. This concept rests on the assumption that dose-response curves for individual patients, as well as for populations, are similar in shape: if many patients display no response at low doses but suddenly respond dramatically to some dose higher than the [quot]decision point dose[quot], then the concept is invalid; this hypothesis is testable in future trials.