In-vivo Pharmacokinetics Of Trastuzumab Emtansine (T-DM1) In Cynomolgus Monkeys

As a first line medication on breast cancer,the application of transtuzumab has significantly prolonged the overall survival and progression free survival of Her2 positive patients.However,the drug tolerance is a quite challenge problem.T-DM1 is composed by covalently combining trastuzumab with microtubule inhibitor DM1 via the linker SMCC.By the targeting property of the antibody portion,DM1 is transferred to the target site and released in the tumor cells,thus the tumor cells can be killed.Since T-DM1 has a different effect mechanism,the drug tolerance related to transtuzumab' s downstream signal transduction could be overcome.We have conducted some pre-clinical researches for T-DM1,including rat pharmacokinetics(PK)study,rat acute toxicity study,single dose cynomolgus monkey PK study,and repeat dose cynomolgus monkey PK study.Thereafter,for total antibody and antibody-drug conjugates,based on the result of monkey PK study,we did human PK projection by using allometric model and species-invariant time method.For DM1 and its metabolites,because there is no available mathematics model for unconjugated drug part of antibody-drug conjugates,we summarized some researches related to human PK projection which use physiologically based Pharmacokinetic model as a tool.Meanwhile,we also discussed how to build an appropriate model for antibody-drug conjugates,so that we can predict human PK and disposition of the crucial analysis by using pre-clinical data and some software platforms.Then,the predicted data can be used to support the dosages selection for first-in-human trials.