Brazil China Japan RussiaSpain

Clinical relevance of BCRP inhibition in causing drug-drug interactions (DDIs)

A recent research paper published in the journal of Drug Metabolism & Disposition and co-authored by Dr Rob Elsby, the Head of Cyprotex’s Drug Transporter Team, has confirmed the important role that solitary inhibition of the intestinal BCRP efflux transporter plays towards causing clinically observed DDIs with BCRP substrates such as rosuvastatin.

In the article (Elsby et al., (2016); epub 23 Dec 2015;, fostamatinib (a BCRP inhibitor) was used as an in vivo tool for performing a mechanistic clinical BCRP interaction study with rosuvastatin. The resulting clinically significant 2-fold increase in rosuvastatin exposure (AUC), due to solitary inhibition of intestinal BCRP, confirms the critical role that BCRP plays in rosuvastatin absorption and underlines the impact that inhibition of BCRP has in instigating clinically relevant DDIs. Furthermore, mechanistic static predictions of rosuvastatin AUC increases for the known DDIs listed on the Crestor (rosuvastatin) US FDA drug label suggested that intestinal BCRP inhibition (not hepatic OATP1B1) is the major mechanism underlying these DDIs in the clinic.

From a drug development perspective, in vitro assessment of transporter inhibition is usually performed in the time period following healthy volunteer studies and before going into patients. However, if statins are considered to be critical co‑medications for a particular therapeutic indication, and since inhibition of intestinal BCRP also impacts on the exposure of two other statins, namely atorvastatin and fluvastatin (Elsby et al., 2012; Clin Pharmacol Ther 92:584-598;, then it may be prudent to include in vitro assessment of BCRP inhibition (alongside OATP1B1 inhibition) earlier during candidate selection to understand statin DDI potential when shortlisting.

Cyprotex specialise in regulatory DDI studies and have experience in designing in vitro DDI studies, data generation and reporting for in vitro DDI packages and calculation of AUC predictions that would be valuable towards understanding the statin DDI potential of your molecule.