Journal
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
Volume 6, Issue 4, Pages 228-238Publisher
WILEY
DOI: 10.1002/psp4.12168
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Funding
- Bristol-Myers Squibb
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Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP) 1B1 (Inhibition constant (K-i) similar to 1.1 and 0.014 mu M, respectively) and OATP1B3 (K-i similar to 0.3 and 0.007 mu M, respectively), with cyclosporine also inhibiting intestinal breast cancer resistance protein (BCRP; K-i similar to 0.07 mu M). The predicted effects of gemfibrozil and its metabolite were moderate (1.88-fold increase in rosuvastatin AUC) and mediated primarily via inhibition of hepatic OATP1B1 and renal organic cation transporter 3. This model of rosuvastatin will be useful in prospectively predicting transporter-mediated DDIs with novel pharmaceutical agents in development.
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