title: Regulatory Forum Commentary* Counterpoint: Dose Selection for Tg.rasH2 Mouse Carcinogenicity Studies.
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.
authors.affiliation: Laboratoires Merck Sharp and Dohme-Chibret, Riom, France jarig_darbes@merck.com.
authors.forename: Jarig
authors.initials: J
authors.lastname: Darbes
authors.affiliation: Merck and Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.affiliation: Merck and Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: DeGeorge
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D008297:Male
keywords: Carcinogenicity; Tg.rasH2; maximum tolerated dose.; mouse; preclinical safety-assessment/risk management