Mechanistically Coupled PK (MCPK) Model to Describe Enzyme Induction and Occupancy Dependent DDI of Dabrafenib Metabolism.

ABSTRACT: Dabrafenib inhibits the cell proliferation of metastatic melanoma with the oncogenic BRAF(V600)-mutation. However, dabrafenib monotherapy is associated with pERK reactivation, drug resistance, and consequential relapse. A clinical drug-dose determination study shows increased pERK levels upon daily administration of more than 300 mg dabrafenib. To clarify whether such elevated drug concentrations could be reached by long-term drug accumulation, we mechanistically coupled the pharmacokinetics (MCPK) of dabrafenib and its metabolites. The MCPK model is qualitatively based on in vitro and quantitatively on clinical data to describe occupancy-dependent CYP3A4 enzyme induction, accumulation, and drug-drug interaction mechanisms. The prediction suggests an eight-fold increase in the steady-state

SUBMITTER: Albrecht M 

PROVIDER: S-EPMC8875124 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature