title: Investigating Transporter-Mediated Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin.
abstract: 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 (Ki) ∼1.1 and 0.014 µM, respectively) and OATP1B3 (Ki∼0.3 and 0.007 µM, respectively), with cyclosporine also inhibiting intestinal breast cancer resistance protein (BCRP; Ki∼0.07 µM). 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.
authors.affiliation: Quantitative Clinical Pharmacology, Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Quantitative Clinical Pharmacology, Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Quantitative Clinical Pharmacology, Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: T
authors.initials: T
authors.lastname: Leil
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D061605:Administration, Intravenous; D000284:Administration, Oral; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015248:Gemfibrozil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D008962:Models, Theoretical; D009363:Neoplasm Proteins / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000068718:Rosuvastatin Calcium / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016572:Cyclosporine; D000068718:Rosuvastatin Calcium; D015248:Gemfibrozil; D012293:Rifampin