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Do We Need to Optimize Protein Binding in Drug Discovery?

DMPK. Do We Need to Optimize Protein Binding in Drug Discovery? . NEDMDG Summary Meeting June 4, 2013 Xingrong Liu, Ph.D. Genentech. Free drug interacts with drug targets: Plasma. Total IC 50 = 0.3- 300x K i. Free IC 50 = 0.1-10x K i. Liu et al., Drug Metab Dispos 37:1548–1556, 2009.

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Do We Need to Optimize Protein Binding in Drug Discovery?

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  1. DMPK Do We Need to Optimize Protein Binding in Drug Discovery? NEDMDG Summary Meeting June 4, 2013 Xingrong Liu, Ph.D. Genentech

  2. Free drug interacts with drug targets: Plasma Total IC50 = 0.3- 300x Ki Free IC50 = 0.1-10x Ki Liu et al., Drug Metab Dispos 37:1548–1556, 2009

  3. Brain binding does not contribute to the activity: free drug interacts with drug targets Total IC50 = 1-1000x Ki Free IC50 = 0.3-3x Ki Liu et al., Drug Metab Dispos 37:1548–1556, 2009

  4. Different effects of protein binding on in vitro and in vivo free concentrations In vitro In vivo Scenario 1 fu=0.5 fu ↑Clin↔ fu=0.1 Cbound fu=0.5 Cbound fu=0.1 Cu↔ Cbound fu ↑ fu=0.5 Cu ↑ Cbound Cu ↑ Cu Cu Scenario 2 fu ↑Clin↓

  5. Increase of free fraction by 15X increases IV free AUC by 3X • 3X increase was due to reduced clearance fup=0.01 fup=0.15

  6. Increase of free fraction by 15X increases oral free AUC 2X • 2X increase was due to reduced clearance fup=0.01 fup=0.15

  7. Protein binding vs. intrinsic clearance R = -(CH2)nCH3 n = 0-8 Data form Blakey et al., J Pharmacokinet Biopharm 25:277–312, 1997

  8. Protein binding vs. Vdss R = -(CH2)nCH3 n = 0-8 Data form Blakey et al., J Pharmacokinet Biopharm 25:277–312, 1997

  9. Protein binding vs. t1/2 R = -(CH2)nCH3 n = 0-8 Data form Blakey et al., J Pharmacokinet Biopharm 25:277–312, 1997

  10. Protein binding vs. intrinsic clearance Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008

  11. Protein binding vs. Vdss Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008

  12. Protein binding not associate with t1/2 Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008

  13. Brain unbound conc. is governed by the BBB and plasma unbound conc. Clefflux: efflux transport activity at the BBB PS: diffusion permeability at the BBB

  14. Protein binding does not associate with brain penetration R2=0.077 R2=0.087 Modified from Maurer et al, Drug Metab Dispos 33: 165, 2005

  15. Significant effects of P-gp on brain concentration Compound Efflux Compound Efflux 18 CsA 16-28 Digoxin Desloratadine 14 14-27 8 Verapamil Ivermectin Chen et al, Curr Drug Metab, 4: 272, 2003

  16. Considerations of protein binding in drug discovery • No need to specifically optimize plasma binding • Reduction of plasma protein binding alone does not increase free drug concentration • Reduction of clearance increases free drug concentration • Reduction of plasma protein binding tends to associated with reduction of clearance, as both of the parameters are governed by lipophilicity • No need to specifically optimize brain binding • Reduction of brain tissue binding alone does not increase free brain drug concentration • Reduction of efflux activity enhance free brain drug concentration • Need to consider protein binding in … • PK/PD, human PK/dose/DDI prediction, drug transporter/tissue penetration, safety margin calculation, regulatory filing, etc.

  17. Marcel Hop Bruce Roth Joe Lyssikatos R. Scott Obach Franco Lombardo Nigel J. Waters Dennis A. Smith DMPK Acknowledgements

  18. Protein binding of marketed drugs n = 267 n=14, fu<0.1 Data from Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th

  19. Many successful CNS drugs show high brain binding Modified from Maurer et al, Drug Metab Dispos 33: 165, 2005

  20. Plasma and brain binding has a significant impact on the B/P ratio Total Brain/Plasma Ratio Acid: 0.5 (0.4-0.6) Base: 6 ± 7 (0.1-24) Neutral: 0.9 ± 0.7 (0.2-0.8) 240x Acid: 0.2 (0.2-0.3) Base: 1 ± 0.7 (0.1-3.4) Neutral: 0.5 ± 0.3 (0.1-1) Unbound Brain/Plasma Ratio 34x Modified from Maurer et al, Drug Metab Dispos 33: 165, 2005

  21. Protein binding vs. clearance Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008

  22. Protein binding vs. free Vdss Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008

  23. Questions for protein binding • PPB non-linearity – saturation of PPB as a strategy to increase unbound concentration – is this a viable strategy? • Covalent modifiers – does PPB even matter? Is it always total plasma concentration? • What about "exceptions to the rule"? - e.g. Active transport? Non-well stirred assumption? • Impact on Cmax and Cmin – this could be sensitive to fu – see Derendorf paper I circulated • Determination of unbound PK parameters (Clunbound – Vd,ssunbound) – does this simplify or complicate things? • Species differences? • What should we use PPB data for in drug discovery?

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