Abstract

Purpose: Rosuvastatin (Crestor®) is a commonly prescribed lipid-lowering agent from the statin drug class for the treatment of primary hyperlipidemia and hypertriglyceridemia. It may be coprescribed with another lipid-lowering drug such as gemfibrozil due to their complementary effect. Rosuvastatin is a substrate of multiple transporters including organic anion transporting polypeptides 1B1 (OATP1B1), 1B3 (OATP1B3), 2B1 (OATP2B1), as well as sodium-taurocholate cotransporting polypeptide (NTCP) and breast cancer resistance protein (BCRP), and exhibits minor metabolic clearance. Gemfibrozil is an inhibitor of the OATP1B1 transporter, which accounts for ~50% of the active liver uptake clearance of rosuvastatin. Studies have reported that concomitant administration of statins and gemfibrozil is associated with an increased risk of myopathy and rare but life-threatening rhabdomyolysis, possibly caused by increased systemic exposure of statins. Patients with genetic polymorphisms may be at a higher risk of severe drug interactions when rosuvastatin and gemfibrozil are coprescribed. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model of rosuvastatin following oral administration, and to apply this model to predict the transporter-mediated drug-drug interactions with gemfibrozil.

Methods:

• The GastroPlus™ 9.0 (Simulations Plus, Inc.) Advanced Compartmental Absorption and Transit™ (ACAT™) model was used in conjunction with the PBPKPlus™ and Metabolism and Transporter modules to build a mechanistic absorption/PBPK model for rosuvastatin.
• Physicochemical and biochemical parameters that predict absorption and distribution were obtained from literature [1] or were predicted from structure with ADMET Predictor™ 7.2 (Simulations Plus, Inc.).
• Human organ weights, volumes, and blood perfusion rates were generated by the Population Estimates for Age-Related (PEAR™) Physiology™ module.
• All tissues except the liver were modeled as perfusion-limited tissues. Tissue/plasma partition coefficients (Kps) of perfusion-limited tissues were calculated using the Berezhkovskiy method [2] based on tissue composition and in vitro and in silico physicochemical properties.
• Intestinal passive absorption, BCRP-mediated active efflux, and enterohepatic circulation of rosuvastatin were incorporated in the PBPK model. The permeability limited liver model included active sinusoidal uptake, passive diffusion, metabolism, and biliary secretion mediated by active canalicular efflux (Figure 1).
• in vitro Km values for OATP1B1, OATP1B3, NTCP and BCRP transporters were obtained from literature [3-5]. Vmax values for the liver uptake transporters were fitted against in vivo data to match estimated contribution of each transporter (~50% for OATP1B1, ~35% for NTCP and ~16% for OATP1B3) to the total active hepatic uptake of rosuvastatin [5-6].
• The model was validated by comparing simulated and observed plasma concentration-time profiles for parent drug across several different dose levels following single and multiple oral administrations obtained from literature [7-12].
• Intestinal passive absorption and metabolic clearance both in gut (CYP3A4) as well in permeability-limited liver (CYP3A4 and UGT2B7) were included in gemfibrozil model. MRP transporter-mediated biliary secretion, renal clearance, enterohepatic circulation and parent to metabolite interconversion were incorporated in disposition of gemfibrozil glucuronide metabolite.
• OATP1B1 and NTCP transporter-mediated drug-drug interactions were predicted with the GastroPlus DDI module through dynamic simulations using the validated rosuvastatin and gemfibrozil PBPK models
• IC50 for gemfibrozil inhibition of rosuvastatin OATP1B1- and NTCP-mediated liver uptake was from the literature [5,10]

Sixth Annual American Conference on Pharmacometrics (ACoP) Annual Meeting: October 4-7, 2015, Crystal City, VA

By Joyce S. Macwan, Viera Lukacova, Grazyna Fraczkiewicz, Michael B. Bolger