Prediction of the optimum clinical dosing schedule for menogaril from results with tumor-bearing mice.
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.
Anticancer and Antimicrobials Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
M
M
Yoshida
T
T
Kobunai
K
K
Nakano
H
H
Saito
T
T
Toko
S
S
Takeda
N
N
Unemi
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008297:Male; D017290:Menogaril / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008815:Mice, Inbred Strains; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D017290:Menogaril