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The clinical pharmacology of ondansetron
1Department of Human Pharmacology, Glaxo Group Research Limited, Greenford, Middlesex, U.K.
Abstract:
Ondansetron, a 5-HT3 antagonist proposed for use in the treatment of chemotherapy-induced emesis, was first given to man in 1984 and in the 4 years subsequent to this, the drug was given to more than 220 different healthy volunteers. In pharmacodynamic studies, there was evidence to suggest that ondansetron was gastroprokinetic but reduced transit time through the small bowel. Ondansetron was of no benefit in a model of motion sickness. The pharmacokinetics of ondansetron have been defined in volunteers using intravenous and oral dosage regimens proposed for the clinic. Ondansetron had a terminal plasma half-life of 3.0-3.5 h and plasma clearance (principally metabolic) of the order of 600 ml/min, and there was no evidence of accumulation at steady state. The absolute oral bioavailability of ondansetron was 59%. Metabolic studies showed the drug to be excreted predominantly in urine and faeces, with a metabolite profile in urine similar to that seen in the animal species used for toxicological testing. Ondansetron is both safe and well tolerated at daily doses of up to 64 mg given to volunteers.
Insights
Ondansetron, a 5-HT3 antagonist, effectively manages chemotherapy-induced nausea and vomiting. Studies in healthy volunteers show it is safe and well-tolerated, with defined pharmacokinetics and bioavailability.
Area of Science:
- Pharmacology
- Gastroenterology
- Clinical Trials
Background:
- Ondansetron is a 5-HT3 antagonist investigated for chemotherapy-induced emesis.
- The drug was administered to over 220 healthy volunteers between 1984 and 1988.
Purpose of the Study:
- To evaluate the pharmacodynamics and pharmacokinetics of ondansetron in humans.
- To assess the safety and tolerability of ondansetron in healthy volunteers.
Main Methods:
- Pharmacodynamic studies assessing gastroprokinetic effects and transit time.
- Pharmacokinetic analysis using intravenous and oral administration.
- Metabolic and excretion profiling.
Main Results:
- Ondansetron demonstrated gastroprokinetic effects and reduced small bowel transit time.
- Pharmacokinetics showed a terminal half-life of 3.0-3.5 h and clearance of 600 ml/min.
- Absolute oral bioavailability was 59%, with no accumulation at steady state.
Conclusions:
- Ondansetron is safe and well-tolerated in healthy volunteers at doses up to 64 mg daily.
- The drug's pharmacokinetic and metabolic profiles are defined for clinical use.
- Ondansetron is effective for chemotherapy-induced emesis but not motion sickness.