Advertisement

Absorption, Distribution, Metabolism, and Excretion of Biopharmaceutical Drug Products

  • Molly Graveno
  • Robert E. StratfordJr.
Chapter

Abstract

Biopharmaceuticals are playing an increasing role in therapy; as a subset of therapeutics, their proportional use relative to traditional small drugs is increasing in terms of sales and volume. Often termed biotherapeutics, this drug class is primarily represented by protein pharmaceuticals, which includes a wide range of drug sizes covering 1000–150,000 dalton (Da) molecular weight. Given their relatively large size and their hydrophilic nature and susceptibility to hydrolytic degradation in tissues throughout the body (as opposed to primarily renal and hepatic elimination of small drugs), their absorption, distribution, metabolism, and excretion (ADME) properties are different in many aspects. This chapter will describe these properties in detail for protein biopharmaceuticals. This presentation will include strategies to mitigate their susceptibility to hydrolysis in order to increase their bioavailability and prolong their residence time in the body. As well, the important role of modification of the physicochemical properties of proteins in influencing rate of their absorption and exposure-time profile will be discussed in the context of insulin and insulin analogs for the treatment of diabetes mellitus. The chapter will conclude with a relatively brief discussion of the ADME properties of heparin, a carbohydrate-based biopharmaceutical, and those associated with the combined cell- and gene-based therapy of two recently marketed products for the treatment of refractory blood-borne cancers.

Keywords

Biopharmaceutical Biotherapeutic Heparin disposition Insulin delivery Monoclonal antibody drug Protein drug Peptide drug Gene delivery Biotherapeutic disposition Monoclonal antibody disposition 

References

  1. Agerso H, Seiding Larsen L, Riis A et al (2004) Pharmacokinetics and renal excretion of desmopressin after intravenous administration to healthy subjects and renally impaired patients. Br J Clin Pharmacol 58:352–358CrossRefGoogle Scholar
  2. Ait-Oudhia S, Ovacik MA, Mager DE (2017) Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity. MAbs 9:15–28CrossRefGoogle Scholar
  3. Alt N, Zhang TY, Motchnik P et al (2016) Determination of critical quality attributes for monoclonal antibodies using quality by design principles. Biologicals 44:291–305CrossRefGoogle Scholar
  4. Bara L, Billaud E, Gramond G et al (1985) Comparative pharmacokinetics of a low molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 39:631–636CrossRefGoogle Scholar
  5. Beshyah SA, Anyaoku V, Niththyananthan R et al (1991) The effect of subcutaneous injection site on absorption of human growth hormone: abdomen versus thigh. Clin Endocrinol 35:409–412CrossRefGoogle Scholar
  6. Binder C (1969) Absorption of injected insulin. A clinical-pharmacological study. Acta Pharmacol Toxicol (Copenh) 27:1–84CrossRefGoogle Scholar
  7. Bjornsson TD, Wolfram KM, Kitchell BB (1982) Heparin kinetics determined by three assay methods. Clin Pharmacol Ther 31:104–113CrossRefGoogle Scholar
  8. Boss AH, Petrucci R, Lorber D (2012) Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. J Diabetes Sci Technol 6:773–779CrossRefGoogle Scholar
  9. Bumbaca D, Boswell CA, Fielder PJ et al (2012) Physiochemical and biochemical factors influencing the pharmacokinetics of antibody therapeutics. AAPS J 14:554–558CrossRefGoogle Scholar
  10. Chirmule N, Jawa V, Meibohm B (2012) Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J 14:296–302CrossRefGoogle Scholar
  11. Cui Y, Cui P, Chen B et al (2017) Monoclonal antibodies: formulations of marketed products and recent advances in novel delivery system. Drug Dev Ind Pharm 43:519–530CrossRefGoogle Scholar
  12. De Swart CA, Numeyer B, Roelofs JM et al (1982) Kinetics of intravenously administered heparin in normal humans. Blood 60:1251–1258PubMedGoogle Scholar
  13. Di L (2015) Strategic approaches to optimizing peptide ADME properties. AAPS J 17:134–143CrossRefGoogle Scholar
  14. Dirks NL, Meibohm B (2010) Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49:633–659CrossRefGoogle Scholar
  15. Drewe J, Meier R, Vonderscher J et al (1992) Enhancement of the oral absorption of cyclosporin in man. Br J Clin Pharmacol 34:60–64CrossRefGoogle Scholar
  16. Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705CrossRefGoogle Scholar
  17. Duckworth WC, Bennett RG, Hamel FG (1998) Insulin degradation: progress and potential. Endocr Rev 19:608–624PubMedGoogle Scholar
  18. Ghetie V, Ward ES (1997) FcRn: the MHC class I-related receptor that is more than an IgG transporter. Immunol Today 18:592–598CrossRefGoogle Scholar
  19. Goeddel DV, Kleid DG, Bolivar F et al (1979) Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc Natl Acad Sci U S A 76:106–110CrossRefGoogle Scholar
  20. Goetze AM, Liu YD, Zhang Z et al (2011) High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology 21:949–959CrossRefGoogle Scholar
  21. Heinemann L, Muchmore DB (2012) Ultrafast-acting insulins: state of the art. J Diabetes Sci Technol 6:728–742CrossRefGoogle Scholar
  22. Hirsh J, Raschke R (2004) Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:188S–203SCrossRefGoogle Scholar
  23. Home PD (2012) The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes Metab 14:780–788CrossRefGoogle Scholar
  24. Home PD (2015) Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabetes Obes Metab 17:1011–1020CrossRefGoogle Scholar
  25. Hunter J (2008) Subcutaneous injection technique. Nurs Stand 22:41–44PubMedGoogle Scholar
  26. Igawa T, Tsunoda H, Tachibana T et al (2010) Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel 23:385–392CrossRefGoogle Scholar
  27. Jackisch C, Muller V, Maintz C et al (2014) Subcutaneous administration of monoclonal antibodies in oncology. Geburtshilfe Frauenheilkd 74:343–349CrossRefGoogle Scholar
  28. Kagan L (2014) Pharmacokinetic modeling of the subcutaneous absorption of therapeutic proteins. Drug Metab Dispos 42:1890–1905CrossRefGoogle Scholar
  29. Keizer RJ, Huitema AD, Schellens JH et al (2010) Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49:493–507CrossRefGoogle Scholar
  30. Kraynov E, Kamath AV, Walles M et al (2016) Current approaches for absorption, distribution, metabolism, and excretion characterization of antibody-drug conjugates: an industry white paper. Drug Metab Dispos 44:617–623CrossRefGoogle Scholar
  31. Krishna M, Nadler SG (2016) Immunogenicity to biotherapeutics – the role of anti-drug immune complexes. Front Immunol 7:21CrossRefGoogle Scholar
  32. Leader B, Baca QJ, Golan DE (2008) Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 7:21–39CrossRefGoogle Scholar
  33. Lee WA, Ennis RD, Longenecker JP (1994) The bioavailability of intranasal salmon calcitonin in healthy volunteers with and without a permeation enhancer. Pharm Res 11:747–750CrossRefGoogle Scholar
  34. Linhardt RJ, Gunay NS (1999) Production and chemical processing of low molecular weight heparins. Semin Thromb Hemost 25:5–16CrossRefGoogle Scholar
  35. Liu L (2015) Antibody glycosylation and its impact on the pharmacokinetics and pharmacodynamics of monoclonal antibodies and Fc-fusion proteins. J Pharm Sci 104:1866–1884CrossRefGoogle Scholar
  36. Liu L (2018) Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell 9:15–32CrossRefGoogle Scholar
  37. Liu L, Stadheim A, Hamuro L et al (2011) Pharmacokinetics of IgG1 monoclonal antibodies produced in humanized Pichia pastoris with specific glycoforms: a comparative study with CHO produced materials. Biologicals 39:205–210CrossRefGoogle Scholar
  38. Lobo ED, Hansen RJ, Balthasar JP (2004) Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 93:2645–2668CrossRefGoogle Scholar
  39. Mach H, Gregory SM, Mackiewicz A et al (2011) Electrostatic interactions of monoclonal antibodies with subcutaneous tissue. Ther Deliv 2:727–736CrossRefGoogle Scholar
  40. Mager DE (2006) Target-mediated drug disposition and dynamics. Biochem Pharmacol 72:1–10CrossRefGoogle Scholar
  41. Mi Y, Lin A, Fiete D et al (2014) Modulation of mannose and asialoglycoprotein receptor expression determines glycoprotein hormone half-life at critical points in the reproductive cycle. J Biol Chem 289:12157–12167CrossRefGoogle Scholar
  42. Moots RJ, Xavier RM, Mok CC et al (2017) The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: results from a multinational, real-world clinical practice, non-interventional study. PLoS One 12:e0175207CrossRefGoogle Scholar
  43. Mueller KT, Maude SL, Porter DL et al (2017) Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood 130:2317–2325CrossRefGoogle Scholar
  44. Nauck M (2016) Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 18:203–216CrossRefGoogle Scholar
  45. Owens DR (2011) Insulin preparations with prolonged effect. Diabetes Technol Ther 13:S5–S14CrossRefGoogle Scholar
  46. Pecoraro V, De Santis E, Melegari A et al (2017) The impact of immunogenicity of TNFalpha inhibitors in autoimmune inflammatory disease. A systematic review and meta-analysis. Autoimmun Rev 16:564–575CrossRefGoogle Scholar
  47. Porter CJ, Charman SA (2000) Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci 89:297–310CrossRefGoogle Scholar
  48. Reddy ST, Berk DA, Jain RK et al (2006) A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles. J Appl Physiol 101:1162–1169CrossRefGoogle Scholar
  49. Richter WF, Jacobsen B (2014) Subcutaneous absorption of biotherapeutics: knowns and unknowns. Drug Metab Dispos 42:1881–1889CrossRefGoogle Scholar
  50. Richter WF, Bhansali SG, Morris ME (2012) Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J 14:559–570CrossRefGoogle Scholar
  51. Roberts ZJ, Better M, Bot A et al (2018) Axicabtagene ciloleucel, a first-in-class CART T cell therapy for aggressive NHL. Leuk Lymphoma 59(8):1785–1796Google Scholar
  52. Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715–725CrossRefGoogle Scholar
  53. Salar A, Avivi I, Bittner B et al (2014) Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study. J Clin Oncol 32:1782–1791CrossRefGoogle Scholar
  54. Schoch A, Kettenbergher H, Mundigl O et al (2015) Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. Proc Natl Acad Sci U S A 112:5997–6002CrossRefGoogle Scholar
  55. Sedelmeier G, Sedelmeier J (2017) Top 200 drugs by worldwide sales 2016. Chimia (Aarau) 71:730CrossRefGoogle Scholar
  56. Shah DK, Betts AM (2013) Antibody biodistribution coefficients: inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human. MAbs 5:297–305CrossRefGoogle Scholar
  57. Shpilberg O, Jackisch C (2013) Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase. Br J Cancer 109:1556–1561CrossRefGoogle Scholar
  58. Smith A, Manoli H, Jaw S (2016) Unraveling the effect of immunogenicity on the PK/PD, efficacy, and safety of therapeutic proteins. J Immunol Res 2016:9: ID 2342187CrossRefGoogle Scholar
  59. Supersaxo A, Hein WR, Steffen H (1990) Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm Res 7:167–169CrossRefGoogle Scholar
  60. Ter Braak EW, Woodworth JR, Bianchi R et al (1996) Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care 19:1437–1440CrossRefGoogle Scholar
  61. Tibbitts J, Canter D, Graff R et al (2016) Key factors influencing ADME properties of therapeutic proteins: a need for ADME characterization in drug discovery and development. MAbs 8:229–245CrossRefGoogle Scholar
  62. Usmani SS, Bedi G, Samuel JS et al (2017) THPdb: database of FDA-approved peptide and protein therapeutics. PLoS One 12:e0181748CrossRefGoogle Scholar
  63. Vezina HE, Cotreau M, Han TH et al (2017) Antibody-drug conjugates as cancer therapeutics: past, present, and future. J Clin Pharmacol 57:S11–S25CrossRefGoogle Scholar
  64. Wang W, Wang EQ, Balthasar JP (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548–558CrossRefGoogle Scholar
  65. Wu F, Bhansali SG, Law WC et al (2012) Fluorescence imaging of the lymph node uptake of proteins in mice after subcutaneous injection: molecular weight dependence. Pharm Res 29:1843–1853CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Duquesne University School of Pharmacy (MG)PittsburghUSA
  2. 2.Clinical PharmacologyIndiana University School of Medicine (RES)IndianapolisUSA

Personalised recommendations