Search

Aims: In man a neurokinin-1 (NK1) receptor antagonist has previously been shown to be ineffective in the prevention of motion-induced nausea. The antiemetic efficacy of NK1 receptor antagonists against chemotherapy-induced emesis is, however, enhanced when combined with a 5-HT3 receptor antagonist. Hence the efficacy of the NK1 antagonist GR205171 in combination with the 5-HT3 antagonist ondansetron (Zofrantrade mark) was assessed in motion-induced nausea., Methods: GR205171 25 mg i.v., with and without concomitant administration of ondansetron 8 mg i.v., and hyoscine hydrobromide 0. 6 mg orally (positive control) were compared with placebo in a model of motion-induced nausea. The study was performed to a four-period, randomized, balanced, double-blind, crossover design in 16 healthy subjects. The end-point was the exposure to the motion stimulus required to produce moderate nausea in the subjects., Results: The motion stimulus required to produce moderate nausea was significantly greater for the positive control than placebo (P < 0. 001). There was no significant difference between either GR205171 or GR205171 plus ondansetron and placebo (P = 0.648 and 0.342, respectively)., Conclusions: The enhancement of NK1 receptor antagonist antiemetic activity through combination with a 5-HT3 receptor antagonist is not replicated in motion-induced nausea.

This open-label, randomized, two-way crossover study compared the relative heterogeneity in systemic availability of oral ondansetron and granisetron. It was conducted in 10 healthy male and 10 healthy female subjects aged 18 to 50 years. Following an overnight fast, each subject received 8 mg ondansetron and 1 mg granisetron. Treatments were separated by 7 days. Blood samples for drug assay were collected over a period of 36 h and variability in pharmacokinetic parameter estimates were assessed following standardization by their respective means. Granisetron showed significantly more variability than ondansetron in the three primary endpoints of the area under the curve extrapolated to infinite time, the area under the curve to the last quantifiable time point, and maximal concentration (p =.0032,.0037, and.0042, respectively). In one subject, concentrations of granisetron were detectable but below the lower limit of quantitation at any time point. The impact this variability may have on therapeutic efficacy is not clear. An apparent bimodal distribution in granisetron AUC infinite, which appeared to be related to smoking was observed. Because granisetron has been reported to be metabolized primarily by the cytochrome P-450 (CYP) 3A isozyme family in humans, it is possible that cigarette smoke could be an inducer of CYP3A or that CYP1A2, also implicated in the metabolism of granisetron and known to be induced by smoking, is more important in the biotransformation of granisetron than previously thought.

Aims: To construct a population model to account for the variability in ondansetron pharmacokinetics and to evaluate methods for the efficient development of population models., Methods: Population models were developed using 99 subjects consisting of paediatric patients, young, elderly and aged volunteers. A two compartment pharmacokinetic model with a zero order input was used to describe the pharmacokinetics of ondansetron. Three stepwise methods were proposed and used alongside a three step approach to develop population models with both rich and sparse data sets. The stepwise methods were based on obtaining empirical Bayes posterior estimates of pharmacokinetic parameters within a nonlinear mixed effect modelling (NONMEM) program. The parameters were then regressed against covariates in a stepwise procedure. Variance parameters were obtained by fitting the proposed population model to the data in one further NONMEM run. The population model was validated against a test data set of 54 subjects, including children, young and elderly patients and volunteers., Results: The population model adequately described the differences in ondansetron pharmacokinetics between paediatric patients, young, elderly and aged volunteers. Different covariates were identified by the various methods. Weight was found to have a strong positive linear relationship with all four pharmacokinetic parameters. Clearance showed a weak negative relationship with age. Males were found to have a greater clearance than females after weight adjustment., Conclusions: The stepwise search procedures potentially are capable of considerably reducing the time required to develop population pharmacokinetic models. The model developed for ondansetron gave accurate predictions of both the concentration-time profile and variability in an independent data set.

The physiology of emesis has been studied for several hundred years, focusing on the different centres involved and the mechanics of expulsion. The vomiting centre receives inputs from various emetic detectors such as the gut, the vestibular labyrinths and the chemoreceptor trigger zone. Emesis is a common disabling effect in motion sickness, postoperative conditions and in radio- and chemotherapy. Our current understanding of the mechanisms has been provided mainly by the recent introduction of serotonin 5-HT3 receptor antagonists into therapeutic use. Nevertheless, despite the considerable advances made in the understanding of the different pathways involved in emesis, there are number of areas that still require experimental investigation. Different animal and human models are available to study the physiology of emesis and to evaluate the antiemetic activity of new compounds, but they need to be predictors of clinical situations.

The objective of this study was to determine the effects of ondansetron on the pharmacokinetics of temazepam and on pharmacodynamics relevant to its use as oral premedication. Twenty-four healthy volunteers (12 of each sex) were administered the following oral treatments in a randomised, double-blind crossover design: temazepam 20 mg plus placebo; or temazepam 20 mg plus ondansetron 8 mg. Blood samples were taken for plasma temazepam assay at intervals up to 32 h after administration. In addition, a brief battery of psychomotor tests was administered 1 h prior to dosing and 1 and 4 h after dosing. Analysis of the derived pharmacokinetic parameters showed no differences between the treatments described above. Analysis of data from the dynamic measures likewise showed no difference between the treatments. It was concluded that the co-administration of ondansetron did not influence the pharmacokinetics or pharmacodynamic actions of temazepam.

Ondansetron is a 5-hydroxytryptamine3 receptor antagonist for the treatment of chemotherapy- and radiotherapy-induced nausea and emesis. A sensitive, accurate, and precise HPLC method for the determination of ondansetron in plasma is described. Samples are prepared by solid-phase extraction and, after chromatography of the extracts on a silica analytical column, ondansetron is detected by UV absorbance at 305 nm. The method is sensitive down to 1 ng/mL, at which concentration the coefficient of variation was 6.2% in a single assay run. Repeated analyses of quality control samples, nominally at 2 ng/mL, were carried out over a number of assay runs with a coefficient of variation of 5.5%. The method is specific for ondansetron with respect to endogenous plasma components, identified phase I metabolites, and some co-administered chemotherapeutic drugs. In sustained use over several months, and in support of the clinical development of ondansetron, the method has been shown to be robust. An application of the assay in the investigation of the pharmacokinetics of ondansetron in the young and elderly is described.