A computational dynamic model of combination treatment for type II inhibitors with asciminib
Despite continuous strides forward in drug development, resistance to treatment looms large in the battle against cancer as well as communicable diseases. Chronic myeloid leukaemia (CML) is treated with targeted therapy and treatment is personalised when resistance arises. It has been extensively studied and is used as a model for targeted therapy. In this work, we examine combination treatments of type II Abl1 inhibitors and asciminib (an allosteric regulator) through a computational model at patient relevant concentrations. Due to the separate binding sites of type II inhibitors and asciminib, we propose their combination treatment as potentially robust to resistance. We find that the simultaneous cobinding of type II inhibitors and asciminib is high in synergetic combinations. As an aid to designing and comparing combination treatments, we put forward an equation that expands on the effective ratio of IC50 (ERIC). Unlike usual comparisons of IC50 values, ERIC takes takes patient plasma concentrations into account. The product of two ERIC values (ERICcombo) creates comparable approximations of the effectiveness of combination treatments with low levels of synergy or antagonism at different concentrations. Its simple formulation is done without experiments and requires less computation and input data than the current standard of ZIP values. As such, the new scheme is a useful complement to experiments that deal with synergy in drug use.