Receptor occupancy theory-based analysis of antiemetic effects and standard doses of 5-HT3 receptor antagonists in cancer patients.

Abstract

PURPOSE:

The aim of this study was to determine the usefulness of receptor occupancy theory-based analysis using pharmacokinetic and pharmacodynamic parameters for predicting the average receptor occupancy (PhiB) in humans of each of five 5-HT3 antagonists administered at standard doses.

METHODS:

The relationship between the PhiB value and the complete vomiting inhibition rate after a single intravenous administration of cisplatin (not less than 50 mg/m2) was analyzed.

RESULTS:

The predicted PhiB values after intravenous administration and oral administration of 5-HT3 antagonists were more than 65% and 50%, respectively, suggesting that relatively high receptor occupancy is required to elicit sufficient antiemetic effects of 5-HT3 antagonists. Moreover, significant ( P<0.05) linear relationships were found between PhiB values and complete vomiting inhibition rates of 5-HT3 antagonists in preventive cisplatin therapy, with correlation coefficients higher than 0.9, suggesting that the 5-HT3 receptor occupancy is an appropriate index of clinical efficacy of 5-HT3 antagonists, with higher receptor occupancy indicating more extensive antiemetic action.

CONCLUSION:

The receptor occupancy theory-based analysis of the antiemetic effect of a 5-HT3 receptor antagonist used in this study should be very useful for not only estimating a rational dosage regimen but also determining the standard dose of a new drug using experimental data obtained in a preclinical study.

• Authors: Yasuhiko Yamada, Munetoshi Sugiura, Kozue Higo, Takeshi Ozeki, Risa Takayanagi, Kiyoshi Okuyama, Koujirou Yamamoto, Hitoshi Satoh, Yasufumi Sawada, Tatsuji Iga
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 54 Issue 2 Pg. 185-90 (Aug 2004) ISSN: 0344-5704 [Print] Germany
• PMID: 15168080 (Publication Type: Journal Article)

Chemical References

• Antiemetics
• Antineoplastic Agents
• Receptors, Serotonin, 5-HT3
• Serotonin 5-HT3 Receptor Antagonists
• Cisplatin

Topics

• Antiemetics (pharmacology)
• Antineoplastic Agents (administration & dosage, adverse effects)
• Area Under Curve
• Cisplatin (administration & dosage, adverse effects)
• Forecasting
• Humans
• Infusions, Intravenous
• Models, Theoretical
• Receptors, Serotonin, 5-HT3 (drug effects, physiology)
• Serotonin 5-HT3 Receptor Antagonists
• Vomiting