Relationships between Ondansetron Systemic Exposure and Antiemetic Efficacy and Safety in Cancer Patients Receiving Cisplatin

Abstract

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.

The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron

“…Because ondansetron has a relatively low toxicity, interactions with inhibitors of drug metabolism are not likely to cause clinical problems. However, the reduction of plasma concentrations of ondansetron can result in reduced antiemetic efficacy because there is evidence to suggest that the efficacy of ondansetron is dependent on its plasma concentrations 7 , 8 . Furthermore, in the case of an especially strong emetogenic stimulus, higher than usual plasma concentrations of ondansetron are required to obtain the same level of antiemetic control 8 …”

“…Patients with cancer often use many drugs in combination and thus are susceptible to drug interactions. The reduction of plasma concentrations of ondansetron may lead to impaired antiemetic control 7 , 8 . We have therefore examined the possible interaction between rifampin and orally and intravenously administered ondansetron.…”

Clinical Pharmacokinetics of Ondansetron. A Review

“…A similar trend was seen in other patients receiving cisplatin ( L a m s et a1 1990). In a study of 55 cancer patients receiving cisplatin, AUC was estimated using a calculation based on the plasma concentration 4 h after a dose of ondansetron (Pritchard & Wells 1992). The risk of emesis was greatest for patients with a small AUC and a high dose of cisplatin.…”