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Prediction of the optimum clinical dosing schedule for menogaril from results with tumor-bearing mice
M Yoshida1, T Kobunai, K Nakano
1Anticancer and Antimicrobials Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Abstract:
Menogaril is an antitumor agent active after oral administration, and unlike other anthracyclines, extravasation cannot occur. When the IC90 values of menogaril were plotted versus exposure time on a double-logarithmic scale, the regression lines had slopes between -0.64 and -0.80. These results showed that the mode of action of menogaril was type lb, dependent on the area under the curve (AUC) of concentration versus time, like Adriamycin. In calculations that simulated pharmacokinetic findings if administration were for three consecutive days (the single dose given was 79 mg/kg) or on days 1 and 8 (the single dose was 238 mg/kg), the peak tumor concentration of menogaril was 1870 and 2985 ng/g and the AUC was 68,363 and 89,352 ng/g hour, respectively. Of the dosing schedules tried, these two dosing schedules were the optimum, with satisfactory antitumor activity against mouse solid tumor Colon 26 and with a wide range of effective dose concentrations. Since menogaril was AUC-dependent, it was possible to predict antitumor activity and to choose optimum dosing schedules on the basis of cell-kill kinetic and pharmacokinetic information.
Insights
Menogaril, an oral antitumor drug, demonstrates type lb action dependent on the area under the curve (AUC). Optimal dosing schedules were identified for effective antitumor activity against mouse solid tumors.
Area of Science:
- Pharmacology
- Oncology
- Drug Discovery
Background:
- Menogaril is an orally administered antitumor agent.
- Unlike other anthracyclines, menogaril does not cause extravasation.
- Its mechanism of action is characterized as type lb, similar to Adriamycin.
Purpose of the Study:
- To determine the pharmacokinetic and pharmacodynamic properties of menogaril.
- To identify optimal dosing schedules for menogaril based on its AUC-dependent activity.
- To evaluate the antitumor efficacy of menogaril against a mouse solid tumor model.
Main Methods:
- IC90 values were plotted against exposure time on a double-logarithmic scale to determine the mode of action.
- Pharmacokinetic simulations were performed for different dosing schedules (three consecutive days vs. days 1 and 8).
- Antitumor activity was assessed against mouse solid tumor Colon 26.
Main Results:
- Menogaril exhibits type lb, area under the curve (AUC)-dependent activity.
- Simulated dosing schedules resulted in peak tumor concentrations of 1870-2985 ng/g and AUCs of 68,363-89,352 ng/g*hour.
- Two specific dosing schedules demonstrated satisfactory antitumor activity and a wide range of effective concentrations.
Conclusions:
- Menogaril's antitumor activity is dependent on the area under the curve (AUC).
- Pharmacokinetic and cell-kill kinetic data can predict antitumor activity and optimize dosing regimens.
- The identified dosing schedules offer a promising approach for menogaril's therapeutic use.