Abstract
High-dose selection for 6-month carcinogenicity studies of pharmaceutical candidates in Tg.rasH2-transgenic mice currently primarily relies on (1) estimation of a maximum tolerated dose (MTD) from the results of a 1-month range-finding study, (2) determination of the maximum dose administrable to the animals (maximum feasible dose [MFD]), (3) demonstration of a plateau in systemic exposure, and (4) use of a limit dose of 1,500 mg/kg/day for products with human daily doses not exceeding 500 mg. Eleven 6-month Tg.rasH2 carcinogenicity studies and their corresponding 1-month range-finding studies conducted at Merck were reviewed. High doses were set by estimation of the MTD in 6, by plateau of exposure in 3, and by MFD in 2 cases. For 4 of 6 studies where MTD was used for high-dose selection, the 1-month study accurately predicted the 6-month study tolerability whereas in the remaining 2 studies the high doses showed poorer tolerability than expected. The use of 3 or more drug-treated dose levels proved useful to ensure that a study would successfully and unambiguously demonstrate that a drug candidate was adequately evaluated for carcinogenicity at a minimally toxic high dose level, especially when the high dose may be found to exceed the MTD.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
