Semi-mchanistic pk/pd modelling in oncology drug development

Resum

Semi mechanistic PK/PD modelling in oncology drug development The present work involves the pharmacokinetic / pharmacodynamic (pk/pd) characterisation of novel compounds of a new class of anticancer drugs (the signal pathways modulators) in early pharmaceutical development. Ly2157299 a TGF-B ri inhibitor was administered orally twice a day to nude mice inoculated with human xenografts. Two different experiments were performed PK/PD which provided information about plasma levels of the drug, and percentage of inhibition of phosphorylation of psmad. The second experiment followed the tumour size during 25 to 30 days after the 1st administration. Drug disposition was described with a two compartment model. An indirect response model was used inhibition of psmad. The inhibition of tumour growth observed in the animals treated with the durg was linked to the percentage inhibition of psmad using a propagation time (MSPT). The model was validated with additional data, and provided a tool to generate a new experimental hypothesis to gain a better insight into mechanisms of signal transduction induced or associated to the TGF- B type I receptors. LY2401401 an antiangiogenic drug was studied. It was found there different process that contributed with the elimination. A linear time and concentration independent process, a concentration dependent process, and a time dependent process. The tumour growth inhibition model was similar to the one described to TGF-B inhibitor, but in this case the signal responsible of reducing tumour size needed to be amplified by a non- linear function