Evaluation of BCRP-Related DDIs Between Methotrexate and Cyclosporin A Using Physiologically Based Pharmacokinetic Modelling

Background and objective: This study provides a physiologically based pharmacokinetic (PBPK) model-based analysis of the potential drug-drug interaction (DDI) between cyclosporin A (CsA), a breast cancer resistance protein transporter (BCRP) inhibitor, and methotrexate (MTX), a putative BCRP substrate.

Methods: PBPK models for CsA and MTX were built using open-source tools and published data for both model building and for model verification and validation. The MTX and CsA PBPK models were evaluated for their application in simulating BCRP-related DDIs. A qualification of an introduced empirical uniform in vitro scaling factor of K_i values for transporter inhibition by CsA was conducted by using a previously developed model of rosuvastatin (sensitive index BCRP substrate), and assessing if corresponding DDI ratios were well captured.

Results: Within the simulated DDI scenarios for MTX in the presence of CsA, the developed models could capture the observed changes in PK parameters as changes in the area under the curve ratios (area under the curve during DDI/area under the curve control) of 1.30 versus 1.31 observed and the DDI peak plasma concentration ratios (peak plasma concentration during DDI/peak plasma concentration control) of 1.07 versus 1.28 observed. The originally reported in vitro K_i values of CsA were scaled with the uniform qualified scaling factor for their use in the in vivo DDI simulations to correct for the low intracellular unbound fraction of the CsA effector concentration. The resulting predicted versus observed ratios of peak plasma concentration and area under the curve DDI ratios with MTX were 0.82 and 0.99, respectively, indicating adequate model accuracy and choice of a scaling factor to capture the observed DDI.

Conclusions: All models have been comprehensively documented and made publicly available as tools to support the drug development and clinical research community and further community-driven model development.