Effect of dose regimen on the toxicity of 2'-deoxy-2'-methylidenecytidine (DMDC) in monkeys.
2'-deoxy-2'-methylidenecytidine (DMDC) is a potential anticancer deoxycytidine analog of cytosine arabinoside. Using monkeys, we conducted a 4-week toxicity study with toxicokinetics of DMDC at 1, 3, and 10 mg/kg/day and a dose-regimen study of three different schedules of once-daily administration (5 mg/kg/day) for 1 week every 2 weeks, 2 weeks every 4 weeks, and 3 weeks every 4 weeks. Deaths, myelosuppression, intestinal toxicity, and swelling of palm and sole skin were observed by oral DMDC treatment at 10 mg/kg/day in 4-week repeated toxicity study; however, no skin disorders have been reported in humans. No notable changes were observed at 1 and 3 mg/kg/day. The curves of dose vs. AUC and the AUC at MTD in monkey are similar to those in humans. In the dose-regimen study, all the toxicities were reversible but more severe toxicity was observed with the longer administration periods. One-week interruption showed sufficient recovery of decreased WBC in dosing regimens of 1-week-on/1-week-off and 2-weeks-on/2-weeks-off. A 2-week recovery period was almost sufficient for the recovery of decreased RBC, HCT, and skin disorders in the 2-weeks-on/2-weeks-off regimen. Therefore, once-daily for 2 weeks every 4 weeks was concluded to be the optimal dose regimen. In summary, myelosuppression, intestinal toxicity, and skin disorders were observed in DMDC treatment in monkeys, the relationship between AUC and toxicity in monkeys was close to that in humans, and in preclinical studies, it is advantageous to investigate optimal dose regimens using the appropriate species.
Shindoh
Hidetoshi
H
Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan. shindohdt@chugai-pharm.co.jp
Kawashima
Akira
A
Shishido
Nobuyuki
N
Nakano
Kounosuke
K
Kobayashi
Kazuko
K
Horii
Ikuo
I
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D003841:Deoxycytidine; C056034:2'-deoxy-2'-methylenecytidine