Relationships between ondansetron systemic exposure and antiemetic efficacy and safety in cancer patients receiving cisplatin.

Single concentration estimators of systemic exposure to the serotonin type 3 receptor antagonist and antiemetic, ondansetron, were established in 55 cancer patients receiving cisplatin-based chemotherapy plus a daily regimen of ondansetron given every 4 h for 3 doses on each day of chemotherapy. Ondansetron plasma concentration measured 4 h after the first daily dose of ondansetron (C[4h]) proved to be a reliable index of AUC and hence of systemic exposure. In patients receiving dosages of cisplatin < 95 mg/m2, the risk of emesis was greatest among those with the lowest systemic exposure to ondansetron. Most patients (64%) experienced emesis if C[4h] was < 20 ng/ml, whereas emesis did not occur in any patient with C[4h] > 80 ng/ml. Among patients receiving very high dosages of cisplatin (> 95 mg/m2), comparable levels of systemic exposure were not totally effective in preventing emesis. For these patients, more ondansetron was required to block the greater emetic stimulus produced by higher doses of cisplatin. This difference reflects a shift in the log exposure versus response relationship, and is consistent with serotonin antagonism at a receptor. In contrast, reported side effects of ondansetron were not related to exposure.