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Research ArticlePerspective

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions—an Industry Perspective

Tonika Bohnert, Aarti Patel, Ian Templeton, Yuan Chen, Chuang Lu, George Lai, Louis Leung, Susanna Tse, Heidi J Einolf, Ying-Hong Wang, Michael Sinz, Ralph Stearns, Robert Walsky, Wanping Geng, Sirimas Sudsakorn, David Moore, Ling He, Jan Wahlstrom, Jim Keirns, Rangaraj Narayanan, Dieter Lang, Xiaoqing Yang and International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Victim Drug-Drug Interactions Working Group
Drug Metabolism and Disposition August 2016, 44 (8) 1399-1423; DOI: https://doi.org/10.1124/dmd.115.069096
Tonika Bohnert
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Aarti Patel
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Ian Templeton
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Yuan Chen
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Chuang Lu
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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George Lai
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Louis Leung
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Susanna Tse
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Heidi J Einolf
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Ying-Hong Wang
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Michael Sinz
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Ralph Stearns
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Robert Walsky
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Wanping Geng
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Sirimas Sudsakorn
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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David Moore
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Ling He
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Jan Wahlstrom
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Jim Keirns
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Rangaraj Narayanan
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Dieter Lang
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Xiaoqing Yang
Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Abstract

Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

Footnotes

    • Received December 18, 2015.
    • Accepted March 31, 2016.
  • dx.doi.org/10.1124/dmd.115.069096.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (8)
Drug Metabolism and Disposition
Vol. 44, Issue 8
1 Aug 2016
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Research ArticlePerspective

New Molecular Entities as Victims of Metabolic Drug-Drug Interactions

Tonika Bohnert, Aarti Patel, Ian Templeton, Yuan Chen, Chuang Lu, George Lai, Louis Leung, Susanna Tse, Heidi J Einolf, Ying-Hong Wang, Michael Sinz, Ralph Stearns, Robert Walsky, Wanping Geng, Sirimas Sudsakorn, David Moore, Ling He, Jan Wahlstrom, Jim Keirns, Rangaraj Narayanan, Dieter Lang, Xiaoqing Yang and International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Victim Drug-Drug Interactions Working Group
Drug Metabolism and Disposition August 1, 2016, 44 (8) 1399-1423; DOI: https://doi.org/10.1124/dmd.115.069096

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Research ArticlePerspective

New Molecular Entities as Victims of Metabolic Drug-Drug Interactions

Tonika Bohnert, Aarti Patel, Ian Templeton, Yuan Chen, Chuang Lu, George Lai, Louis Leung, Susanna Tse, Heidi J Einolf, Ying-Hong Wang, Michael Sinz, Ralph Stearns, Robert Walsky, Wanping Geng, Sirimas Sudsakorn, David Moore, Ling He, Jan Wahlstrom, Jim Keirns, Rangaraj Narayanan, Dieter Lang, Xiaoqing Yang and International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Victim Drug-Drug Interactions Working Group
Drug Metabolism and Disposition August 1, 2016, 44 (8) 1399-1423; DOI: https://doi.org/10.1124/dmd.115.069096
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  • Article
    • Abstract
    • Introduction
    • In Vitro Determination of the Enzymes Involved in Metabolizing of a NME and Their Relative Contribution Fm,Enzyme
    • Approaches to Determine Clearance Pathways
    • Application of Modeling and Simulation Tools in Victim NME DDI Predictions
    • General Perspectives and Strategic Recommendations
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