Use of preclinical and early clinical data for dose selection of a selective estrogen receptor modulator toremifene in treatment of breast cancer

摘要

In development of human medicines, it is important to predict early and accurately enoughthe disease and patient population to be treated as well as the effective and safe dose rangeof the studied medicine. This is pursued by using preclinical research models, clinicalpharmacology and early clinical studies with small sample sizes. When successful, thisenables effective development of medicines and reduces unnecessary exposure of healthysubjects and patients to ineffectice or harmfull doses of experimental compounds.Toremifene is a selective estrogen receptor modulator (SERM) used for treatment of breastcancer. Its development was initiated in 1980s when selection of treatment indicationsand doses were based on research in cell and animal models and on noncomparativeclinical studies including small number of patients. Since the early development phase,the treatment indication, the patient population and the dose range were confirmed inlarge comparative clinical studies in patients. Based on the currently available large andlong term clinical study data the aim of this study was to investigate how the early phasestudies were able to predict the treatment indication, patient population and the doserange of the SERM.As a conclusion and based on the estrogen receptor mediated mechanism of action earlystudies were able to predict the treatment indication, target patient population and adose range to be studied in confirmatory clinical studies. However, comparative clinicalstudies are needed to optimize dose selection of the SERM in treatment of breast cancer.