Antitumor activity of targeted and cytotoxic agents in murine subcutaneous tumor models correlates with clinical response.
OBJECTIVE
Immunodeficient mice transplanted with subcutaneous tumors (xenograft or allograft) are widely used as a model of preclinical activity for the discovery and development of anticancer drug candidates. Despite their widespread use, there is a widely held view that these models provide minimal predictive value for discerning clinically active versus inactive agents. To improve the predictive nature of these models, we have carried out a retrospective population pharmacokinetic-pharmacodynamic (PK-PD) analysis of relevant xenograft/allograft efficacy data for eight agents (molecularly targeted and cytotoxic) with known clinical outcome.


METHODS
PK-PD modeling was carried out to first characterize the relationship between drug concentration and antitumor activity for each agent in dose-ranging xenograft or allograft experiments. Next, simulations of tumor growth inhibition (TGI) in xenografts/allografts at clinically relevant doses and schedules were carried out by replacing the murine pharmacokinetics, which were used to build the PK-PD model with human pharmacokinetics obtained from literature to account for species differences in pharmacokinetics.


RESULTS
A significant correlation (r = 0.91, P = 0.0008) was observed between simulated xenograft/allograft TGI driven by human pharmacokinetics and clinical response but not when TGI observed at maximum tolerated doses in mice was correlated with clinical response (r = 0.36, P = 0.34).


CONCLUSIONS
On the basis of these analyses, agents that led to greater than 60% TGI in preclinical models, at clinically relevant exposures, are more likely to lead to responses in the clinic. A proposed strategy for the use of murine subcutaneous models for compound selection in anticancer drug discovery is discussed.
Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA.
Harvey
H
Wong
Edna F
EF
Choo
Bruno
B
Alicke
Xiao
X
Ding
Hank
H
La
Erin
E
McNamara
Frank-Peter
FP
Theil
Jay
J
Tibbitts
Lori S
LS
Friedman
Cornelis E C A
CE
Hop
Stephen E
SE
Gould
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents