Plasma protein binding and blood-free concentrations: Which studies are needed to develop a drug?

Expert Opinion on Drug Metabolism and Toxicology

Volumn 7, Issue 8, 2011, Pages 1009-1020

  Pellegatti, Mario ^a   Pagliarusco, Sabrina ^b   Solazzo, Lara ^b   Colato, Dimitri ^b  

^a GSK   (Italy)

^b Aptuit Inc   (United States)

Author keywords

blood binding; blood cells; drug development; free concentration; pharmacokinetics; plasma protein binding; regulatory requirements

Indexed keywords

AMIODARONE; BINDING PROTEIN; ESTROGEN; GAVESTINEL; OROSOMUCOID; POTASSIUM CHANNEL; POTASSIUM CHANNEL HERG; RADAFAXINE; S 12363; TOPOTECAN; UNCLASSIFIED DRUG; VINCA ALKALOID;

AREA UNDER THE CURVE; BINDING AFFINITY; BRAIN ISCHEMIA; CARCINOGENICITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG PENETRATION; DRUG PROTEIN BINDING; DRUG SAFETY; EQUILIBRIUM DIALYSIS; ESTROGEN BLOOD LEVEL; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; KIDNEY DISEASE; LIQUID CHROMATOGRAPHY; LIVER CIRRHOSIS; LIVER DISEASE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PATIENT SAFETY; PLASMA PROTEIN BINDING; PREGNANT WOMAN; REVIEW; TANDEM MASS SPECTROMETRY;

ANIMALS; BLOOD PROTEINS; DRUG EVALUATION, PRECLINICAL; DRUG INTERACTIONS; HUMANS; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS; PROTEIN BINDING;

EID: 79960495668     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2011.586336     Document Type: Review

References (78)

1. Rowland M, Tozer TM. Clinical pharmacokinetics: concepts and applications. Williams & Wilkins, Philadelphia; 1995
2. Mehavar R. Role of protein binding in pharmacokinetics. Am J Pharm Educ 2005;69(8):1-8
3. Howard ML, Hill JJ, Galluppi GR, McLean MA. Plasma protein binding in drug discovery and development. Comb Chem High Troughput Screen 2010;13:170-87
4. Weiss HM, Fresneau M, Moenius T, et al. Binding of pimecrolimus and tacrolimus to skin and plasma proteins : implication for systemic exposure after topical application. Drug Metab Dispos 2008;36(9):1812-18
5. Wasan KM, Cassidy SM. Role of plasma lipoproteins in modifying the biological activity of hydrophobic drugs. J Pharm Sci 1998;87(4):411-24 (Pubitemid 28175800)
6. Dawidowicz AL, Kobielski M, Pieniadz J. Anomalous relationship between free drug fraction and its total concentration in drug-protein systems II. Binding of different ligands to plasma proteins. Eur J Pharm Sci 2008;35:136-41
7. Berezhkovskiy LM. On the possibility of self-induction of drug protein binding. J Pharm Sci 2010;99:4400-5
8. Herve F, Urien S, Albengres E, et al. Drug binding in plasma: a summary of recent trends in the study of drug and hormone binding. Clin Pharmacokinet 1994;26(1):44-58 (Pubitemid 24029186)
9. Tillement JP, Duche JC, Barre J. Drug binding to blood proteins: characteristics, roles and pathophysiological changes. Bull Acad Natle Med 2006;190(4-5):935-47
10. Trainor GL. The importance of plasma protein binding in drug discovery. Expert Opin Drug Discov 2007;2(1):51-64 (Pubitemid 47078697)
11. Tillement JP, Urien S, Chaumet-Riffaud P, et al. Blood binding and tissue uptake of drugs. Recent advances and perspectives. Fundam Clin Pharmacol 1988;2:223-38
12. Gerskowitch VP, Hodge J, Hull RAD, et al. Unexpected relationship between plasma protein binding and the pharmacodynamics of 2-NAP, a CCK1- receptor antagonist. Br J Clin Pharmacol 2007;63(5):618-22 (Pubitemid 46632566)
13. Boffito M, Back DJ, Blaschke TF, et al. Protein binding in antiretroviral therapies. AIDS Res Hum Retroviruses 2003;19(9):825-35 (Pubitemid 37215138)
14. Spooner N, Lad R, Barfield M. Dried Blood Spots as a sample collection technique for the determination of pharmacokinetics in clinical studies: considerations for the validation of a quantitative bioanalytical method. Anal Chem 2009;81:1557-63
15. Patel P, Mulla H, Tanna S. Facilitating pharmacokinetic studies in children: a new use of dried blood spots. Arch Dis Child 2010;95:484-7
16. Banker MJ, Clark TH. Plasma/serum protein binding determinations. Curr Drug Metab 2008;9:854-9
17. Vuignier K, Schappler J, Veuthey JL, et al. Drug protein binding: a critical review of analytical tools. Anal Bioanal Chem 2010;398:53-66
18. Chuang VTG, Maruyama T, Otagiri M. Updates on contemporary protein binding techniques. Drug Metab Pharmacokinet 2009;24(4):358-64
19. Note for guidance on the investigation of drug interactions CPMP/EWP/560/95 (1997). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.tga.gov.au/docs/ pdf/euguide/ewp/056095en.pdf
20. Guidance on the investigation of drug interactions CPMP/EWP/560/95 Draft (2010). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.ema.europa.eu/docs/en-GB/ document-library/Scientific-guideline/2010/05/WC500090112.pdf
21. Pharmacokinetics in patients with impaired renal function-Study design, data analysis and impact on dosing and labelling Draft (2010). FDA/Center for drug evaluation and research. Available from: www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM204959.pdf
22. Pharmacokinetics in patients with impaired hepatic function -Study design, data analysis and impact on dosing and labelling (2003). FDA/Center for drug evaluation and research. Available from: www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/ucm072123.pdf
23. Goodman and Gilman?s the pharmacological basis of therapeutics. 10th edition. McGraw-Hill, New York; 2001
24. Liu X, Chen C, Hop CECA. Do we need to optimize plasma protein and tissue binding in drug discovery? Curr Top Med Chem 2011;11:450-66
25. Trainor GL. Plasma protein binding and the free drug principle: recent developments and applications. Annu Rep Med Chem 2007;42:489-502
26. Berezhkovskij LM. On the influence of protein binding on pharmacological activity of drugs. J Pharm Sci 2010;99(4):2153-65
27. Braggio S, Montanari D, Rossi T, Ratti E. Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates. Expert Opin Drug Discov 2010;5(7):1-9
28. Summerfield SG, Lucas AJ, Porter RA, et al. Toward an improved prediction of human in vivo brain penetration. Xenobiotica 2008;38(12):1518-35
29. Read KD, Braggio S. Assessing brain free fraction in early drug discovery. Expert Opin Drug Metab Toxicol 2010;6(3):337-44
30. Benko R, Matuz M, Doro P, et al. Pharmacokinetics and pharmacodynamics of levofloxacin in critically ill patients with ventilator-associated pneumonia. Int J Antimicro Ag 2007;30:162-8 (Pubitemid 46992714)
31. Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov 2010;9(12):929-39
32. Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals CPMP/ICH/286/95 (2009). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.ema.europa.eu/docs/en-GB/document-library/ Scientific-guideline/2009/09/WC500002720.pdf
33. Pharmacokinetics and metabolic studies in the safety evaluation of new medical products in animals 3BS11A (1994). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.ema.europa.eu/docs/en-GB/document-library/Scientific-guideline/2009/ 09/WC500002886.pdf
34. Pharmacokinetic studies in man 3CC3a (1988). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.tga.gov.au/DOCS/pdf/euguide/vol3c/3cc3aen.pdf
35. Note for guidance on Toxicokinetics: a guidance for assessing systemic exposure in toxicology studies CPMP/ICH/384/95 (2009). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.ema.europa. eu/docs/en-GB/document-library/Scientific-guideline/2009/ 09/WC500002770.pdf
36. Note for guidance on dose selection for carcinogenicity studies of pharmaceuticals EMEA/CHMP/ICH/383/1995 (2008). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.ema.europa.eu/docs/en-GB/document-library/Scientific-guideline/2009/ 09/WC500002768.pdf
37. Lumpkin MH, Bruckner JV, Campbell JL, et al. Plasma binding of thrichloroacetic acid in mice, rats and humans under cancer bioassay and environmental exposure conditions. Drug Metab Dispos 2003;31:1203-7 (Pubitemid 37152970)
38. Kajbaf M, Barnaby RJ, Bottacini M, et al. Pharmacokinetics, metabolism and excretion of the glycine antagonist GV150526A in rat and dog. Xenobiotica 2003;33:415-28 (Pubitemid 36688117)
39. Hoke JF, Dyker AG, Barnaby RJ, Lees KR. Pharmacokinetics of a glycine site antagonist (gavestinel) following multiple dosing in patients with acute stroke. Eur J Clin Pharmacol 2000;55:867-72 (Pubitemid 30201770)
40. Iavarone L, Hoke JF, Bottacini M, et al. First time in human for GV196771: interspecies scaling applied on dose selection. J Clin Pharmacol 1999;39:560-6 (Pubitemid 30629035)
41. Dyker AG, Lees KR. Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl- D-aspartate receptor) in patients with acute stroke. Stroke 1999;30(5):986-92 (Pubitemid 29211615)
42. Webster R, Leishman D, Walker D. Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr Opin Drug Discov Devel 2002;5(1):116-26 (Pubitemid 34453249)
43. Barre J, Riant P, Tillement JP. Measurement of free drug in phase 1: is it useful? Fundam Clin Pharmacol 1990;4(S2):141s-50s
44. Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function CHMP/EWP/225/02 (2004). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.ema.europa.eu/docs/en-GB/document-library/ Scientific-guideline/2009/09/WC500003123.pdf
45. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function CPMP/EWP/2339/02 (2005). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.tga.gov.au/docs/pdf/euguide/ewp/233902en. pdf
46. Palatini P, Orlando R, De Martin S. The effect of liver disease on inhibitory and plasma protein-binding displacement interactions: an update. Expert Opin Drug Metab Toxicol 2010;6(10):1215-30
47. Leopold D, Webb D, Buss DC, et al. The ex vivo plasma protein binding of theophylline in renal disease. Br J Clin Pharmacol 1985;19(6):823-5 (Pubitemid 15232152)
48. Verbeeck RK, Cardinal JA, Wallace SM. Effect of age and sex on the plasma binding of acidic and basic drugs. Eur J Clin Pharmacol 1984;27(1):91-7 (Pubitemid 14033886)
49. Guideline on the investigation of medicinal products in the term and preterm neonate. Doc Ref. EMEA/536810/2008 (2009). The European Agency for the Evaluation of Medicinal Products. Human medicines evaluation unit. Available from: www.emea.europa. eu/docs/en-GB/document-library/Scientific-guideline/2009/ 09/WC500003750.pdf
50. Viani A, Rizzo G, Carrai M, Pacifici GM. The effect of aging on plasma albumin and plasma protein binding of diazepam, salicylic acid and digitoxin in healthy subjects and patients with renal impairment. Br J Clin Pharmacol 1992;33(3):299-304
51. Clinical lactation studies - study design; data analysis, and recommendations for labelling. Draft (2005). FDA/Center for drug evaluation and research. Available from www.fda.gov/downloads/RegulatoryInformation/Guidances/ ucm127505.pdf
52. Pharmacokinetics in pregnancy - study design, data analysis and impact on dosing and labelling. Draft (2004). FDA/Center for drug evaluation and research. Available from www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm072133.pdf
53. Rolan PE. Plasma protein binding displacement interactions. Why are they still regarded as clinically important? Br J Clin Pharmacol 1994;37(2):125-8 (Pubitemid 24213753)
54. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002;71(3):115-21 (Pubitemid 34271114)
55. Sandson NB, Marcucci C, Bourke DL, Smith-Lamacchia R. An interaction between aspirin and valproate: the relevance of plasma protein displacement drug-drug interactions. Am J Psychiatry 2006;163(11):1891-6 (Pubitemid 44807780)
56. Christensen H, Baker M, Tucker GT, Rostami-Hodjegan A. Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data. J Pharm Sci 2006;95:2778-87 (Pubitemid 46093184)
57. Israili ZH, Dayton PG. Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab Rev 2001;33(2):161-235 (Pubitemid 32703255)
58. Fuse E, Tanii H, Kurata N, et al. Unexpected clinical pharmacology of UCN-01 caused by specific binding to human alpha1-AGP. Cancer Res 1998;58(15):3248-53 (Pubitemid 28371060)
59. Mealy NE, Bayes M. Radafaxine hydrochloride. Drugs Future 2004;29(9):967 (Pubitemid 39531808)
60. Volcow ND, Wang GJ, Fowler JS, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predicts poor reinforcing effects. Biol Psychiatry 2005;57(6):640-6 (Pubitemid 40409702)
61. Rossato P. Can plasma protein binding represent a safety issue for drug development? The radafaxine case. Drug Metab Rev 2008;40(s3):15
62. Sadler BM, Gillotin C, Lou Y, Stein DS. In vivo effect of alpha1-acid glycoprotein on pharmacokinetics of amprenavir, a human immunodeficiency virus protease inhibitor. Antimicrob Agents Chemother 2001;45(3):852-6 (Pubitemid 32182036)
63. Baille TA, Cayen MN, Fouda H, et al. Drug metabolites in safety testing. Toxicol Appl Pharmacol 2002;182:188-96
64. Atrakchi AH. Interpretation and considerations on the safety evaluation of human drug metabolites. Chem Res Toxicol 2009;22:1217-20
65. Hinderling PH. Red blood cells: a neglected compartment in pharmacokinetics and pharmacodynamics. Pharmacol Rev 1997;49(3):279-94
66. Snoeck E, Piotrovskij V, Jacqmin P, et al. Population analysis of the non linear red blood cell partitioning and the concentration- effect relationship of draflazine following various infusion rates. Br J Clin Pharm 1997;43(6):603-12 (Pubitemid 27283569)
67. Tanaka C, Kawai R, Rowland M. Dose-dependent pharmacokinetics of cyclosporine A in rats: events in tissues. Drug Metab Dispos 2000;28:582-9 (Pubitemid 30238519)
68. Mohammed SS, Christopher MM, Metha P, et al. Increased erythrocyte and protein binding of codeine in patients with sickle cell disease. J Pharm Sci 1993;82(11):1112-17 (Pubitemid 24004441)
69. Highley MS, De Bruijn EA. Erythrocytes and the transport of drugs and endogenous compounds. Pharm Res 1996;13(2):186-95
70. Gneushev ET, Gneusheva IA. The binding of drugs to erythrocytes. Eksp Klin Farmakol 1996;59(5):75 (Pubitemid 126422468)
71. Maling TJB, Siebers RW, Burgess CD, et al. Individual variability of amiodarone distribution in plasma and erythrocytes: implications for therapeutic monitoring. Ther Drug Monit 1989;11:121-6 (Pubitemid 19064834)
72. Urien S, Bastian G, Lucas C, et al. Binding of a new vinca alkaloid derivative, S12363, to human plasma proteins and platelets. Usefulness of an erythrocyte partitioning technique. Invest New Drugs 1992;10:263-8 (Pubitemid 23008972)
73. Loos WJ, Gelberbloom H, Verweij J, et al. Red blood cells: a neglected compartment in topotecan pharmacokinetic analysis. Anticancer Drugs 2003;14(3):227-32 (Pubitemid 36418942)
74. Farowski F, Cornely OA, Vehreschild JJ, et al. Intracellular concentrations of posaconazole in different compartments of peripheral blood. Antimicrob Agents Chemother 2010;54(7):2928-31
75. Berquivist Y, Domeij-Nimberg B. Distribution of chloroquine and its metabolite desethyl-chloroquine in human blood cells and its implication for the quantitative determination of these compounds in serum and plasma. J Chromatogr 1983;272(1):137-48
76. Water NJ, Jones R, Williams G, Sohal B. Validation of a Rapid Equilibrium Dialysis approach for the measurement of plasma protein binding. J Pharm Sci 2008;97(10):4586-95
77. Fura A, Harper TW, Zhang H, et al. Shift in pH of biological fluids during storage and processing: effect on bionalysis. J Pharm Sci 2003;32:513-22 (Pubitemid 38021842)
78. Kochansky CJ, McMasters D, Lu P, et al. Impact of pH on plasma protein binding in equilibrium dialysis. Mol Pharm 2008;5(3):438-48 (Pubitemid 351929828)