Selecting a Suitable Animal Model to Predict the Co-Administration Risk Between Lapatinib and Irinotecan

Selecting a suitable animal model to evaluate lapatinib-irinotecan interaction in human is very important and necessary. The inhibition of lapatinib on the glucuronidation of SN-38 was determined in the liver microsomes from human (HLM), monkey (MLM), rat (RLM), and mice (MyLM). Lapatinib 10 mu M inhibited the glucuronidation of SN-38 by over 80% (p < 0.001) in the HLM incubation system. The similar inhibition extent of lapatinib on the glucuronidation of SN-38 was observed for MyLM incubation system. In RLM and MLM incubation mixture, lapatinib exerted weaker inhibition on the glucuronidation of SN-38. Competitive inhibition of lapatinib on the glucuronidation of SN-38 was observed in MyLM incubation system, and noncompetitive inhibition of lapatinib on the glucuronidation of SN-38 was found in RLM and MLM incubation system. In conclusion, from the perspective of inhibition extent, monkey is suitable animal model for evaluating lapatinib-irinotecan interaction in human. However, from the inhibition kinetic type, mice and rat are the suitable animal model for evaluating lapatinib-irinotecan interaction in human.