Modification of the rosuvastatin model

A PBPK model of rosuvastatin in a European Caucasian healthy volunteer population was previously constructed in Simcyp's drug library. Because Asians show higher systemic exposure of rosuvastatin than do Caucasians [26], the recommended starting dose for Asians (5 mg) is lower than that for Caucasians (10 mg) [27]. Although the cause of these racial differences is unclear, one possible explanation is that there may be differences in the activity or expression levels of uptake transporters of rosuvastatin, such as OATP1B1, OATP1B3, and NTCP, and/or an efflux transporter, such as BCRP. Because the PK data of a telmisartan–rosuvastatin interaction study conducted in Korean healthy volunteers were used as the reference [3], the rosuvastatin model in Simcyp's drug library was modified to reflect PK profiles in Koreans. Using Sensitivity Analysis (SA) and Parameter Estimation (PE) modules, the hepatic uptake clearance values of OATP1B1, OATP1B3, and NTCP for rosuvastatin were modified step-by-step to recover the published mean plasma concentrationtime profile of rosuvastatin in Korean populations [3,31,32] from 5 different studies, whose data were obtained by digitization (Plot Digitizer, version 2.6.6, http://plotdigitizer.sourceforge.net). After these modifications, rosuvastatin concentrations in 10 virtual trials (10 healthy subjects per trial, aged 20–50, male/female=1:1) after a single (20 mg) oral dose were simulated in Simcyp.