Is Ipecac Model a good predictor of concentration-efficacy response to Ondansetron in patients?

C. Veyrat-Follet1,2, E. Fuseau1, R. Farinotti1, J.L. Palmer2

Universiti Paris-Sud, FRANCE, 2 GlaxoWellcome Research and Development, UK.

1Ondansetron is a 5-HT3 receptor antagonist used for the prevention and/or treatment of cancer chemotherapy- and radiotherapy-induced emesis and post-operative nausea and vomiting. Ipecacuanha-induced emesis has been used in healthy subjects for the evaluation of 5-HT3 antagonists. Ondansetron as a 4 mg iv dose is effective in preventing ipecacuanha-induced emesis and nausea.

In order to evaluate the predictability of pharmacokinetic/pharmacodynamic (PK/PD) ipecac model in clinical situations, a large database of studies in healthy volunteers and in patients was constituted. Data were collected from 120 healthy male subjects treated or not with ipecac syrup and 66 patients (43 women) exposed to opioid-induced emesis after surgery via regional anaesthesia. Each volunteer or patient received a single intravenous infusion of 0.1 to 16 mg of ondansetron over 5 minutes. Rescue medication was allowed anytime after study drug administration. Sparse plasma samples from patients and full kinetic profiles from healthy subjects were taken for PK analysis. The time of onset of nausea and emesis, the number of emetic episodes and nausea scores were recorded. The mean age was 28 years and 56 years for the healthy subjects and the patients respectively; the mean weight was 76 kg for the 2 groups and the mean height was 178 cm and 166 cm for the healthy subjects and the patients respectively.

A NONMEM analysis was performed using a two-compartment model and individual Bayesian estimates of PK parameters were obtained. The relationship between the individual PK parameter estimates and covariates were modelled with SPLUS using a generalised additive model (GAM). Finally the population model was built using NONMEM on the basis of the GAM analysis. Then, the relationship between the number of emetic episodes and individual systemic exposure to ondansetron was analysed.

Reference: PAGE 6 () Abstr 588 [www.page-meeting.org/?abstract=588]

Poster: oral presentation