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Predicting Clinical DDIs with Rosuvastatin

The widespread use of statins within the general population, and evidence for their involvement in clinically relevant drug-drug interactions (DDIs), have led to concerns over potential safety when administered concomitantly with other medications. For example, transporter-based DDIs are known to be responsible for increased plasma levels of rosuvastatin, and it has been demonstrated that BCRP inhibition plays a role in this interaction (Elsby et al., 2016; Drug Metab Dispos 44:398-408).

Rosuvastatin is orally administered and, therefore, intestinal absorption is required before the drug reaches the systemic circulation. However, rosuvastatin is a substrate of BCRP and this transporter limits absorption of rosuvastatin across the gastrointestinal tract (Elsby et al., 2012; Clin Pharmacol Ther 92:584-598). Co-administered drugs which inhibit BCRP transport can, therefore, increase absorption of rosuvastatin, potentially doubling intended exposure levels. Because of the risk of DDIs through BCRP interaction, regulatory authorities recommend that in vitro BCRP inhibition studies are performed for all new investigational drugs in order to inform on their clinical development.

Estrone 3-sulfate (E3S) is an accepted in vitro probe substrate for investigating BCRP inhibition potential, but its possible utility as a surrogate probe substrate to predict BCRP-mediated DDIs with rosuvastatin has not been assessed. Research undertaken at Cyprotex compared the use of E3S and rosuvastatin as probe substrates towards assessment of in vitro BCRP inhibition.  A number of perpetrator drugs which inhibit BCRP clinically to cause DDIs with rosuvastatin were assessed, and the resulting [I2]/Ki ratios and clinical DDI risk derived from using each probe were compared.

The data demonstrate that E3S and rosuvastatin are useful probe substrates to identify BCRP inhibition in vitro. Furthermore, the choice of probe substrate can be important towards accurately predicting clinically relevant BCRP inhibition from in vitro data. This may be especially important when developing new therapies for patient populations where statins are likely to be co-administered with the drug being developed.

Our research was recently presented as a poster at the 7th Clinically Relevant Drug Transporter Conference in Berlin on 21-23rd June 2016.

Download the poster.