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.