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The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

Nature Reviews Drug Discovery volume 9, pages 929–939 (2010)Cite this article

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Abstract

Data from in vitro plasma protein binding experiments that determine the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compounds for in vivo studies. However, we consider that these practices are usually misleading, because in vivo efficacy is determined by the free (unbound) drug concentration surrounding the therapeutic target, not by the free drug fraction. These practices yield no enhancement of the in vivo free drug concentration. So, decisions based on free drug fraction could result in the wrong compounds being advanced through drug discovery programmes. This Perspective provides guidance on the application of plasma protein binding information in drug discovery.

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Figure 1: Effects of plasma protein binding on in vitro and in vivo systems.
Figure 2: Effects of free drug fraction on unbound and total area under the plasma concentration–time curve for an orally administered drug.
Figure 3: Effects of structure modification on in vivo exposure.
Figure 4: The plasma protein binding of some of the top 100 most prescribed drugs.

References

  1. Molla, A. et al. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology 250, 255–262 (1998).

    CAS  PubMed  Google Scholar 

  2. Velaparthi, U. et al. Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activity. J. Med. Chem. 51, 5897–5900 (2008).

    CAS  PubMed  Google Scholar 

  3. McKerrecher, D. et al. Design of a potent, soluble glucokinase activator with excellent in vivo efficacy. Bioorg. Med. Chem. Lett. 16, 2705–2709 (2006).

    CAS  PubMed  Google Scholar 

  4. Leach, A. G. et al. Matched molecular pairs as a guide in the optimization of pharmaceutical properties; a study of aqueous solubility, plasma protein binding and oral exposure. J. Med. Chem. 49, 6672–6682 (2006).

    CAS  PubMed  Google Scholar 

  5. Boros, E. E. et al. Synthesis and antiviral activity of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV integrase inhibitors. J. Med. Chem. 52, 2754–2761 (2009).

    CAS  PubMed  Google Scholar 

  6. Benet, L. Z. & Hoener, B.-A. Changes in plasma protein binding have little clinical relevance. Clin. Pharmacol. Ther. 71, 115–121 (2002).

    CAS  PubMed  Google Scholar 

  7. Pang, K. S. & Rowland, M. Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J. Pharmacokinet. Biopharm. 5, 625–653 (1977).

    CAS  PubMed  Google Scholar 

  8. Lin, J. H. CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr. Drug Metab. 9, 46–59 (2008).

    CAS  PubMed  Google Scholar 

  9. Liu, X. et al. Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug Metab. Dispos. 34, 1443–1447 (2006).

    CAS  PubMed  Google Scholar 

  10. Hammarlund-Udenaes, M., Friden, M., Syvanen, S. & Gupta, A. On the rate and extent of drug delivery to the brain. Pharm. Res. 8, 1737–1750 (2008).

    Google Scholar 

  11. Brammer, K. W., Farrow, P. R. & Faulkner, J. K. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev. Infect. Dis. 12, S318–S326 (1990).

    PubMed  Google Scholar 

  12. Schramm, P., Wildfeuer, A. & Sarnow, E. Determination of fluconazole concentrations in the prostatic and seminal vesicle fluid (split ejaculate). Mycoses 37, 417–420 (1994).

    CAS  PubMed  Google Scholar 

  13. Debruyne, D. Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses. Clin. Pharmacokinet. 33, 52–77 (1997).

    CAS  PubMed  Google Scholar 

  14. Day, R. O., Francis, H., Vial, J., Geisslinger, G. & Williams, K. M. Naproxen concentrations in plasma and synovial fluid and effects on prostanoid concentrations. J. Rheumatol. 22, 2295–2303 (1995).

    CAS  PubMed  Google Scholar 

  15. Maurer, T. S., DeBartolo, D. B., Tess, D. A. & Scott, D. O. Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metab. Dispos. 33, 175–181 (2005).

    CAS  PubMed  Google Scholar 

  16. Summerfield, S. G. et al. Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, P-glycoprotein efflux, and free fractions in blood and brain. J. Pharmacol. Exp. Ther. 316, 1282–1290 (2006).

    CAS  PubMed  Google Scholar 

  17. Avdeef, A. Physicochemical profiling (solubility, permeability and charge state). Curr. Top. Med. Chem. 1, 277–351 (2001).

    CAS  PubMed  Google Scholar 

  18. Di, L., Kerns, E. H. & Carter, G. T. Strategies to assess blood–brain barrier penetration. Expert Opin. Drug Discov. 3, 677–687 (2008).

    CAS  PubMed  Google Scholar 

  19. Liu, X., Tu, M., Kelly, R. S., Chen, C. & Smith, B. J. Development of a computational approach to predict blood–brain barrier permeability. Drug Metab. Dispos. 32, 132–139 (2004).

    CAS  PubMed  Google Scholar 

  20. Ziemniak, J. A., Shank, R. G. & Schentag, J. J. The partitioning of cimetidine into canine cerebrospinal fluid. Drug Metab. Dispos. 12, 217–221 (1984).

    CAS  PubMed  Google Scholar 

  21. Suzuki, H., Terasaki, T. & Sugiyama, Y. Role of efflux transport across the blood–brain barrier and blood–cerebrospinal fluid barrier on the disposition of xenobiotics in the central nervous system. Adv. Drug Deliv. Rev. 25, 257–285 (1997).

    CAS  Google Scholar 

  22. Somogyi, A. & Gugler, R. Clinical pharmacokinetics of cimetidine. Clin. Pharmacokinet. 8, 463–495 (1983).

    CAS  PubMed  Google Scholar 

  23. Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumours. Nature Rev. Cancer 6, 583–592 (2006).

    CAS  Google Scholar 

  24. Lau, Y. Y., Huang, Y., Frassetto, L. & Benet, L. Z. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin. Pharmacol. Ther. 81, 194–204 (2007).

    CAS  PubMed  Google Scholar 

  25. Kang, J., Wang, L., Chen, X.-L., Triggle, D. J. & Rampe, D. Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol. Pharmacol. 59, 122–126 (2001).

    CAS  PubMed  Google Scholar 

  26. Webster, R. et al. Pharmacokinetic/pharmacodynamic assessment of the effects of E4031, cisapride, terfenadine, and terodiline on monophasic action potential duration in dog. Xenobiotica 31, 633–650 (2001).

    CAS  PubMed  Google Scholar 

  27. Miyazaki, M., Maekawa, C., Iwanaga, K., Morimoto, K. & Kakemi, M. Bioavailability assessment of disopyramide using pharmacokinetic–pharmacodynamic (PK–PD) modeling in the rat. Biol. Pharm. Bull. 23, 1363–1369 (2000).

    CAS  PubMed  Google Scholar 

  28. Bischoff, U., Schmidt, C., Netzer, R. & Pongs, O. Effects of fluoroquinolones on HERG currents. Eur. J. Pharmacol. 406, 341–343 (2000).

    CAS  PubMed  Google Scholar 

  29. Kalvass, J. C., Olson, E. R., Cassidy, M. P., Selley, D. E. & Pollack, G. M. Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50, u and correlation of in vitro, preclinical, and clinical data. J. Pharmacol. Exp. Ther. 323, 346–355 (2007).

    CAS  PubMed  Google Scholar 

  30. Webster, R., Leishman, D. & Walker, D. Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr. Opin. Drug Discov. Dev. 5, 116–126 (2002).

    CAS  Google Scholar 

  31. Redfern, W. S. et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. [Erratum to document cited in CA139:172923]. Cardiovasc. Res. 63, 186–187 (2004).

    CAS  Google Scholar 

  32. Redfern, W. S. et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58, 32–45 (2003).

    CAS  PubMed  Google Scholar 

  33. Zhang, J. Y. et al. Development of an improved IP1 assay for the characterization of 5-HT2C receptor ligands. Assay Drug Dev. Technol. 8, 106–113 (2010).

    CAS  PubMed  Google Scholar 

  34. Zhu, P. J. et al. A miniaturized glucocorticoid receptor translocation assay using enzymatic fragment complementation evaluated with qHTS. Comb. Chem. High Throughput Screen. 11, 545–559 (2008).

    PubMed  PubMed Central  Google Scholar 

  35. van Steeg, T. J. et al. Influence of plasma protein binding on pharmacodynamics: estimation of in vivo receptor affinities of beta blockers using a new mechanism-based PK–PD modelling approach. J. Pharm. Sci. 98, 3816–3828 (2009).

    CAS  PubMed  Google Scholar 

  36. Jankovic, J. & Tolosa, E. Parkinson's Disease and Movement Disorders 5th edn (Lippincott Williams & Wilkins, Philadelphia, Pennsylvania; 2007).

    Google Scholar 

  37. Savi, P., Nurden, P., Nurden, A. T., Levy-Toledano, S. & Herbert, J. M. Clopidogrel: a review of its mechanism of action. Platelets 9, 251–255 (1998).

    CAS  PubMed  Google Scholar 

  38. Puscas, I., Coltau, M., Baican, M. & Domuta, G. A new concept regarding the mechanism of action of omeprazole. Int. J. Clin. Pharmacol. Ther. 37, 286–293 (1999).

    CAS  PubMed  Google Scholar 

  39. Moss, N. et al. A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties. Bioorg. Med. Chem. Lett. 19, 2206–2210 (2009).

    CAS  PubMed  Google Scholar 

  40. Ratliff, K. S. et al. An automated electrophysiology serum shift assay for Kv channels. Assay Drug Dev. Technol. 6, 243–253 (2008).

    CAS  PubMed  Google Scholar 

  41. Trainor, G. L. The importance of plasma protein binding in drug discovery. Expert Opin. Drug Discov. 2, 51–64 (2007).

    CAS  PubMed  Google Scholar 

  42. Lin, J. H. & Lu, A. Y. H. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol. Rev. 49, 403–449 (1997).

    CAS  PubMed  Google Scholar 

  43. Liu, X. & Chen, C. Strategies to optimize brain penetration in drug discovery. Curr. Opin. Drug. Discov. Devel. 8, 505–512 (2005).

    CAS  PubMed  Google Scholar 

  44. Livingston, D. J. et al. Weak binding of VX-478 to human plasma proteins and implications for anti-human immunodeficiency virus therapy. J. Infect. Dis. 172, 1238–1245 (1995).

    CAS  Google Scholar 

  45. Bilello, J. A. & Drusano, G. L. Relevance of plasma protein binding to antiviral activity and clinical efficacy of inhibitors of human immunodeficiency virus protease. J. Infect. Dis. 173, 1524–1526 (1996).

    CAS  PubMed  Google Scholar 

  46. Geng, B. et al. Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): pyridodiazepine amines. Bioorg. Med. Chem. Lett. 19, 930–936 (2009).

    CAS  PubMed  Google Scholar 

  47. Coleman, P. J. et al. Nonpeptide αvβ3 antagonists. Part 11: discovery and preclinical evaluation of potent αvβ3 antagonists for the prevention and treatment of osteoporosis. J. Med. Chem. 47, 4829–4837 (2004).

    CAS  PubMed  Google Scholar 

  48. Fessey, R. E., Austin, R. P., Barton, P., Davis, A. M. & Wenlock, M. C. in Pharmacokinetic Profiling in Drug Research: Biological, Physicochemical, and Computational Strategies [LogP2004, Lipophilicity Symposium], (ed. B. Testa) 119–141 (Verlag Helvetica Chimica Acta, Zurich, Switzerland, 2006).

    Google Scholar 

  49. Wan, H., Rehngren, M., Giordanetto, F., Bergstroem, F. & Tunek, A. High-throughput screening of drug–brain tissue binding and in silico prediction for assessment of central nervous system drug delivery. J. Med. Chem. 50, 4606–4615 (2007).

    CAS  PubMed  Google Scholar 

  50. Lewis, D. F. V., Jacobs, M. N. & Dickins, M. Compound lipophilicity for substrate binding to human P450s in drug metabolism. Drug Discov. Today 9, 530–537 (2004).

    CAS  PubMed  Google Scholar 

  51. Toutain, P. L. & Bousquet-Melou, A. Free drug fraction vs free drug concentration: a matter of frequent confusion. J. Vet. Pharmacol. Ther. 25, 460–463 (2002).

    CAS  PubMed  Google Scholar 

  52. Boxenbaum, H. in Pharmacokinetic, Pharmacokinetic & Pharmacodynamic Data Analysis: Concepts and Applications 4th edn Vol. 32 (eds Gabrielsson, J. & Weiner, D.) (Swedish Pharmaceutical Press, 2007).

    Google Scholar 

  53. Peletier, L. A., Benson, N. & van der Graaf, P. H. Impact of plasma-protein binding on receptor occupancy: an analytical description. J. Theor. Biol. 256, 253–262 (2009).

    CAS  PubMed  Google Scholar 

  54. Ogino, Y. et al. Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1-cyclohexan]-4-yl]benzimidazole NPY Y5 receptor antagonists. Bioorg. Med. Chem. Lett. 18, 4997–5001 (2008).

    CAS  PubMed  Google Scholar 

  55. Zheng, G. Z. et al. Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists. Bioorg. Med. Chem. Lett. 16, 4936–4940 (2006).

    CAS  PubMed  Google Scholar 

  56. Hattori, K. et al. Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase. J. Med. Chem. 47, 4151–4154 (2004).

    CAS  PubMed  Google Scholar 

  57. Gilligan, P. J. Corticotropin-releasing factor receptor antagonists. Expert Opin. Ther. Pat. 16, 913–924 (2006).

    CAS  PubMed  Google Scholar 

  58. Hilgert, M., Noldner, M., Chatterjee, S. S. & Klein, J. KA-672 inhibits rat brain acetylcholinesterase in vitro but not in vivo. Neurosci. Lett. 263, 193–196 (1999).

    CAS  PubMed  Google Scholar 

  59. Jeffrey, P. & Summerfield, S. G. Challenges for blood–brain barrier (BBB) screening. Xenobiotica 37, 1135–1151 (2007).

    CAS  PubMed  Google Scholar 

  60. Gabrielsson, J. & Green, A. R. Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology. J. Pharmacol. Exp. Ther. 331, 767–774 (2009).

    CAS  PubMed  Google Scholar 

  61. Coleman, R. A. On the mechanism of the persistent action of salmeterol: what is the current position? Br. J. Pharmacol. 158, 180–182 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Vauquelin, G. & Packeu, A. Ligands, their receptors and. plasma membranes. Mol. Cell. Endocrinol. 311, 1–10 (2009).

    CAS  PubMed  Google Scholar 

  63. Mason, R. P., Moiesey, D. M. & Shajenko, L. Cholesterol alters the binding of calcium channel blockers to the membrane lipid bilayer. Mol. Pharmacol. 41, 315–321 (1992).

    CAS  PubMed  Google Scholar 

  64. Kwan, Y. W., Bangalore, R., Lakitsh, M., Glossmann, H. & Kass, R. S. Inhibition of cardiac L-type calcium channels by quaternary amlodipine: implications for pharmacokinetics and access to dihydropyridine binding site. J. Mol. Cell. Cardiol. 27, 253–262 (1995).

    CAS  PubMed  Google Scholar 

  65. Szczuka, A., Wennerberg, M., Packeu, A. & Vauquelin, G. Molecular mechanisms for the persistent bronchodilatory effect of the β2-adrenoceptor agonist salmeterol. Br. J. Pharmacol. 158, 183–194 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Green, S. A., Spasoff, A. P., Coleman, R. A., Johnson, M. & Liggett, S. B. Sustained activation of a G protein-coupled receptor via “anchored” agonist binding. Molecular localization of the salmeterol exosite within the beta 2-adrenergic receptor. J. Biol. Chem. 271, 24029–24035 (1996).

    CAS  PubMed  Google Scholar 

  67. Lee, C. A., Cook, J. A., Reyner, E. L. & Smith, D. A. P-glycoprotein related drug interactions: clinical importance and a consideration of disease states. Expert Opin. Drug Metab. Toxicol. 6, 603–619 (2001).

    Google Scholar 

  68. Schmidt, S., Gonzalez, D. & Derendorf, H. Significance of protein binding in pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 99, 1107–1122 (2010).

    CAS  PubMed  Google Scholar 

  69. Hussein, Z., Evans, A. M. & Rowland, M. Physiologic models of hepatic drug clearance: influence of altered protein binding on the elimination of diclofenac in the isolated perfused rat liver. J. Pharm. Sci. 82, 880–885 (1993).

    CAS  PubMed  Google Scholar 

  70. Wood, A. & Armour, D. The discovery of the CCR5 receptor antagonist, UK-427, 857, a new agent for the treatment of HIV infection and AIDS. Prog. Med. Chem. 43, 239–271 (2005).

    CAS  PubMed  Google Scholar 

  71. Smith, D. A., van de Waterbeemd, H. & Walker, D. K. Pharmacokinetics and Metabolism in Drug Design 2nd edn Vol. 13 (Wiley-VCH, Weinheim 2006).

    Google Scholar 

  72. Kerns, E. H. & Di, L. Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization 56–167 (Elsevier, London; 2008).

    Google Scholar 

  73. McNamara, P. J., Trueb, V. & Stoeckel, K. Ceftriaxone binding to human serum albumin. Indirect displacement by probenecid and diazepam. Biochem. Pharmacol. 40, 1247–1253 (1990).

    CAS  PubMed  Google Scholar 

  74. Pedersen, L. E. & Bonde, J. Displacement of disopyramide from human plasma proteins. Acta Pharmacol. Toxicol. 57, 223–226 (1985).

    CAS  Google Scholar 

  75. Mungall, D. R. et al. Effect of diltiazem on warfarin plasma protein binding. J. Clin. Pharmacol. 24, 264–266 (1984).

    CAS  PubMed  Google Scholar 

  76. Sparreboom, A., Nooter, K., Loos, W. J. & Verweij, J. The (ir)relevance of plasma protein binding of anticancer drugs. Neth. J. Med. 59, 196–207 (2001).

    CAS  PubMed  Google Scholar 

  77. Sellers, E. M. Plasma protein displacement interactions are rarely of clinical significance. Pharmacology 18, 225–227 (1979).

    CAS  PubMed  Google Scholar 

  78. Bjornsson, T. D., Meffin, P. J., Swezey, S. & Blaschke, T. F. Clofibrate displaces warfarin from plasma proteins in man: an example of a pure displacement interaction. J. Pharmacol. Exp. Ther. 210, 316–321 (1979).

    CAS  PubMed  Google Scholar 

  79. Kohl, C. & Steinkellner, M. Prediction of pharmacokinetic drug/drug interactions from in vitro data: interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral anticoagulants. Drug Metab. Dispos. 28, 161–168 (2000).

    CAS  PubMed  Google Scholar 

  80. DeVane, C. L. Clinical significance of drug binding, protein binding, and binding displacement drug interactions. Psychopharmacol. Bull. 36, 5–21 (2002).

    PubMed  Google Scholar 

  81. Sansom, L. N. & Evans, A. M. What is the true clinical significance of plasma protein binding displacement interactions? Drug Saf. 12, 227–233 (1995).

    CAS  PubMed  Google Scholar 

  82. Rolan, P. E. Plasma protein binding displacement interactions — why are they still regarded as clinically important? Br. J. Clin. Pharmacol. 37, 125–128 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. MacKichan, J. J. Protein binding drug displacement interactions: fact or fiction? Clin. Pharmacokinet. 16, 65–73 (1989).

    CAS  PubMed  Google Scholar 

  84. Smith, D. Absorption and Distribution as Factors in Drug Design, in Medicinal Chemistry — Into the Millennium Vol. 264 (eds Campbell M. M. &, Blagbrough, I. S.) 331–344 (Royal Society of Chemistry, Cambridge, UK, 2001).

    Google Scholar 

  85. Yamada, S., Kato, Y., Okura, T., Kagawa, Y. & Kawabe, K. Prediction of alpha 1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia. Biol. Pharm. Bull. 30, 1237–1241 (2007).

    CAS  PubMed  Google Scholar 

  86. Yamada, Y., Ito, K., Nakamura, K., Sawada, Y. & Iga, T. Prediction of therapeutic doses of beta-adrenergic receptor blocking agents based on quantitative structure–pharmacokinetic/pharmacodynamic relationship. Biol. Pharm. Bull. 16, 1251–1259 (1993).

    CAS  PubMed  Google Scholar 

  87. Mathot, R. A. A., Soudijn, W., Breimer, D. D., Ijzerman, A. P. & Danhof, M. Pharmacokinetic–hemodynamic relationships of 2-chloroadenosine at adenosine A1 and A2a receptors in vivo. Br. J. Pharmacol. 118, 369–377 (1996).

    CAS  Google Scholar 

  88. Troke, P. F., Andrews, R. J., Pye, G. W. & Richardson, K. Fluconazole and other azoles: translation of in vitro activity to in vivo and clinical efficacy. Rev. Infect. Dis. 12, S276–S280 (1990).

    CAS  PubMed  Google Scholar 

  89. Smith, D. A. in Microsomes Drug Oxidation (ed. Kaminsky, L. S.) 31–36 (Monduzzi Editore, Bologna, Italy, 2008).

    Google Scholar 

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Acknowledgements

The authors would like to thank B. Harrison, G. Carter, O. McConnell, J. Butera, T. Mansour, M. Troutman, J. Liras and T. Liston for their support and leadership.

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Authors and Affiliations

  1. Dynamics and Metabolism Department, Dennis A. Smith is at the Pharmacokinetics, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9UJ, UK.,

    Dennis A. Smith

  2. Dynamics and Metabolism Department, Li Di is at the Pharmacokinetics, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.,

    Li Di

  3. Edward H. Kerns is at Discovery ADME, 20 Hampton Court, Skillman, New Jersey 08558, USA.,

    Edward H. Kerns

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Smith, D., Di, L. & Kerns, E. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov 9, 929–939 (2010). https://doi.org/10.1038/nrd3287

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