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.