Predictive model for plasma concentration-versus-time profiles of investigational anticancer drugs in patients.
We report a model that provides a strong correlation between mouse toxicity data [mouse lethal dose 10% (LD10)] and human plasma concentration-versus-time (CXT) data for 22 commonly used anticancer agents. Mouse toxicity data (LD10) from two dosing schedules, daily times one and daily times seven, were evaluated for the two mouse strains BDF/1 and Swiss. Data from BDF/1 mice were selected for analysis because they were more abundant. Strong correlations were found between LD10 and human plasma CXT data for both daily times one and daily times seven dosing schedules--ln (CXT) = -1.6504 + [0.8408 X ln (LD10)], r = .84, P less than .0001, and ln (CXT) = -0.0754 + [0.8954 X ln (LD10)], r = .90, P less than .0001, respectively. These correlations may serve as useful models to predict the maximally tolerated dose of an investigational anticancer agent prior to entry into clinical trials and to assist in the selection of clinically relevant in vitro CXTs for new-agent screening against human tumors.
Davis
L E
LE
Pharmacology Research Program, Arizona Cancer Center, College of Medicine, University of Arizona, Tucson 85724.
Alberts
D S
DS
Plezia
P M
PM
Roe
D J
DJ
Griswold
D P
DP
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000633:toxicity; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological
D000970:Antineoplastic Agents