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Published on: December 1, 2020
Prediction of Transporter-Mediated Rosuvastatin Hepatic Uptake Clearance and Drug Interaction in Humans Using
Vineet Kumar1, Mengyue Yin1, Kazuya Ishida1
1Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.).
Abstract:
Suspended, plated, or sandwich-cultured human hepatocytes are routinely used for in vitro to in vivo extrapolation (IVIVE) of transporter-mediated hepatic clearance (CL) of drugs. However, these hepatocyte models have been reported to underpredict transporter-mediated in vivo hepatic uptake CL (CL ) of some drugs. Therefore, we determined whether transporter-expressing cells (TECs) can accurately predict the CL of drugs. To do so, we determined the uptake CL (CL ) of rosuvastatin (RSV) by TECs (organic anion transporting polypeptides/Na+-taurocholate cotransporting polypeptide) and then scaled it to that in vivo by relative expression factor (REF) (the ratio of transporter abundance in human livers and TEC) determined by liquid chromatography tandem mass spectrometry-based quantitative proteomics. Both the TEC and hepatocyte models did not meet our predefined success criteria of predicting within 2-fold the RSV CL value obtained from our positron emission tomography (PET) imaging. However, the TEC performed better than the hepatocyte models. Interestingly, using REF, TECs successfully predicted RSV CL obtained by the hepatocyte models, suggesting that the underprediction of RSV CL by TECs and hepatocytes is due to endogenous factor(s) not present in these in vitro models. Therefore, we determined whether inclusion of plasma (or albumin) in TEC uptake studies improved IVIVE of RSV CL It did, and our predictions were close to or just fell above our lower 2-fold acceptance boundary. Despite this success, additional studies are needed to improve transporter-mediated IVIVE of hepatic uptake CL of drugs. However, using REF and TEC, we successfully predicted the magnitude of PET-imaged inhibition of RSV CL by cyclosporine A. SIGNIFICANCE STATEMENT: We showed that the in vivo transporter-mediated hepatic uptake CL of rosuvastatin, determined by PET imaging, can be predicted (within 2-fold) from in vitro studies in transporter-expressing cells (TECs) (scaled using REF), but only when plasma proteins were included in the in vitro studies. This conclusion did not hold when plasma proteins were absent in the TEC or human hepatocyte studies. Thus, additional studies are needed to improve in vitro to in vivo extrapolation of transporter-mediated drug CL.
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