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


CONCLUSIONS
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.
Yamada
Yasuhiko
Y
Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, 192-0392, Japan. yamada@ps.toyaku.ac.jp
Sugiura
Munetoshi
M
Higo
Kozue
K
Ozeki
Takeshi
T
Takayanagi
Risa
R
Okuyama
Kiyoshi
K
Yamamoto
Koujirou
K
Satoh
Hitoshi
H
Sawada
Yasufumi
Y
Iga
Tatsuji
T
D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D005544:Forecasting; D006801:Humans; D007262:Infusions, Intravenous; D008962:Models, Theoretical; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000502:physiology*; D058831:Serotonin 5-HT3 Receptor Antagonists; D014839:Vomiting
D000932:Antiemetics; D000970:Antineoplastic Agents; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D002945:Cisplatin