Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
ADME Processes in Pharmaceutical Sciences

  • 2182 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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 58:352–358

    Article  CAS  Google Scholar 

  • Ait-Oudhia S, Ovacik MA, Mager DE (2017) Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity. MAbs 9:15–28

    Article  CAS  Google Scholar 

  • Alt N, Zhang TY, Motchnik P et al (2016) Determination of critical quality attributes for monoclonal antibodies using quality by design principles. Biologicals 44:291–305

    Article  CAS  Google Scholar 

  • 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 39:631–636

    Article  CAS  Google Scholar 

  • 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 35:409–412

    Article  CAS  Google Scholar 

  • Binder C (1969) Absorption of injected insulin. A clinical-pharmacological study. Acta Pharmacol Toxicol (Copenh) 27:1–84

    Article  Google Scholar 

  • Bjornsson TD, Wolfram KM, Kitchell BB (1982) Heparin kinetics determined by three assay methods. Clin Pharmacol Ther 31:104–113

    Article  CAS  Google Scholar 

  • 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 6:773–779

    Article  Google Scholar 

  • Bumbaca D, Boswell CA, Fielder PJ et al (2012) Physiochemical and biochemical factors influencing the pharmacokinetics of antibody therapeutics. AAPS J 14:554–558

    Article  CAS  Google Scholar 

  • Chirmule N, Jawa V, Meibohm B (2012) Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J 14:296–302

    Article  CAS  Google Scholar 

  • 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 43:519–530

    Article  CAS  Google Scholar 

  • De Swart CA, Numeyer B, Roelofs JM et al (1982) Kinetics of intravenously administered heparin in normal humans. Blood 60:1251–1258

    PubMed  Google Scholar 

  • Di L (2015) Strategic approaches to optimizing peptide ADME properties. AAPS J 17:134–143

    Article  CAS  Google Scholar 

  • Dirks NL, Meibohm B (2010) Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49:633–659

    Article  CAS  Google Scholar 

  • Drewe J, Meier R, Vonderscher J et al (1992) Enhancement of the oral absorption of cyclosporin in man. Br J Clin Pharmacol 34:60–64

    Article  CAS  Google Scholar 

  • Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705

    Article  CAS  Google Scholar 

  • Duckworth WC, Bennett RG, Hamel FG (1998) Insulin degradation: progress and potential. Endocr Rev 19:608–624

    CAS  PubMed  Google Scholar 

  • Ghetie V, Ward ES (1997) FcRn: the MHC class I-related receptor that is more than an IgG transporter. Immunol Today 18:592–598

    Article  CAS  Google Scholar 

  • 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 76:106–110

    Article  CAS  Google Scholar 

  • 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 21:949–959

    Article  CAS  Google Scholar 

  • Heinemann L, Muchmore DB (2012) Ultrafast-acting insulins: state of the art. J Diabetes Sci Technol 6:728–742

    Article  Google Scholar 

  • Hirsh J, Raschke R (2004) Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:188S–203S

    Article  CAS  Google Scholar 

  • Home PD (2012) The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes Metab 14:780–788

    Article  CAS  Google Scholar 

  • Home PD (2015) Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabetes Obes Metab 17:1011–1020

    Article  CAS  Google Scholar 

  • Hunter J (2008) Subcutaneous injection technique. Nurs Stand 22:41–44

    PubMed  Google Scholar 

  • Igawa T, Tsunoda H, Tachibana T et al (2010) Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel 23:385–392

    Article  CAS  Google Scholar 

  • Jackisch C, Muller V, Maintz C et al (2014) Subcutaneous administration of monoclonal antibodies in oncology. Geburtshilfe Frauenheilkd 74:343–349

    Article  CAS  Google Scholar 

  • Kagan L (2014) Pharmacokinetic modeling of the subcutaneous absorption of therapeutic proteins. Drug Metab Dispos 42:1890–1905

    Article  Google Scholar 

  • Keizer RJ, Huitema AD, Schellens JH et al (2010) Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49:493–507

    Article  CAS  Google Scholar 

  • 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 44:617–623

    Article  CAS  Google Scholar 

  • Krishna M, Nadler SG (2016) Immunogenicity to biotherapeutics – the role of anti-drug immune complexes. Front Immunol 7:21

    Article  Google Scholar 

  • Leader B, Baca QJ, Golan DE (2008) Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 7:21–39

    Article  CAS  Google Scholar 

  • Lee WA, Ennis RD, Longenecker JP (1994) The bioavailability of intranasal salmon calcitonin in healthy volunteers with and without a permeation enhancer. Pharm Res 11:747–750

    Article  CAS  Google Scholar 

  • Linhardt RJ, Gunay NS (1999) Production and chemical processing of low molecular weight heparins. Semin Thromb Hemost 25:5–16

    Article  CAS  Google Scholar 

  • Liu L (2015) Antibody glycosylation and its impact on the pharmacokinetics and pharmacodynamics of monoclonal antibodies and Fc-fusion proteins. J Pharm Sci 104:1866–1884

    Article  CAS  Google Scholar 

  • Liu L (2018) Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell 9:15–32

    Article  CAS  Google Scholar 

  • 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 39:205–210

    Article  CAS  Google Scholar 

  • Lobo ED, Hansen RJ, Balthasar JP (2004) Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 93:2645–2668

    Article  CAS  Google Scholar 

  • Mach H, Gregory SM, Mackiewicz A et al (2011) Electrostatic interactions of monoclonal antibodies with subcutaneous tissue. Ther Deliv 2:727–736

    Article  CAS  Google Scholar 

  • Mager DE (2006) Target-mediated drug disposition and dynamics. Biochem Pharmacol 72:1–10

    Article  CAS  Google Scholar 

  • 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 289:12157–12167

    Article  CAS  Google Scholar 

  • 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:e0175207

    Article  Google Scholar 

  • 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 130:2317–2325

    Article  CAS  Google Scholar 

  • 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 18:203–216

    Article  CAS  Google Scholar 

  • Owens DR (2011) Insulin preparations with prolonged effect. Diabetes Technol Ther 13:S5–S14

    Article  Google Scholar 

  • 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 16:564–575

    Article  CAS  Google Scholar 

  • Porter CJ, Charman SA (2000) Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci 89:297–310

    Article  CAS  Google Scholar 

  • 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 101:1162–1169

    Article  CAS  Google Scholar 

  • Richter WF, Jacobsen B (2014) Subcutaneous absorption of biotherapeutics: knowns and unknowns. Drug Metab Dispos 42:1881–1889

    Article  Google Scholar 

  • Richter WF, Bhansali SG, Morris ME (2012) Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J 14:559–570

    Article  CAS  Google Scholar 

  • 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):1785–1796

    Google Scholar 

  • Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715–725

    Article  CAS  Google Scholar 

  • 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 32:1782–1791

    Article  CAS  Google Scholar 

  • 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 112:5997–6002

    Article  CAS  Google Scholar 

  • Sedelmeier G, Sedelmeier J (2017) Top 200 drugs by worldwide sales 2016. Chimia (Aarau) 71:730

    Article  CAS  Google Scholar 

  • 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 5:297–305

    Article  Google Scholar 

  • Shpilberg O, Jackisch C (2013) Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase. Br J Cancer 109:1556–1561

    Article  CAS  Google Scholar 

  • 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 2342187

    Article  Google Scholar 

  • Supersaxo A, Hein WR, Steffen H (1990) Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm Res 7:167–169

    Article  CAS  Google Scholar 

  • 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 19:1437–1440

    Article  Google Scholar 

  • 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 8:229–245

    Article  CAS  Google Scholar 

  • Usmani SS, Bedi G, Samuel JS et al (2017) THPdb: database of FDA-approved peptide and protein therapeutics. PLoS One 12:e0181748

    Article  Google Scholar 

  • Vezina HE, Cotreau M, Han TH et al (2017) Antibody-drug conjugates as cancer therapeutics: past, present, and future. J Clin Pharmacol 57:S11–S25

    Article  CAS  Google Scholar 

  • Wang W, Wang EQ, Balthasar JP (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548–558

    Article  CAS  Google Scholar 

  • 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 29:1843–1853

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Duquesne University School of Pharmacy (MG), Pittsburgh, PA, USA

    Molly Graveno

  2. Clinical Pharmacology, Indiana University School of Medicine (RES), Indianapolis, IN, USA

    Robert E. Stratford Jr.

Authors
  1. Molly Graveno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert E. Stratford Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Molly Graveno .

Editor information

Editors and Affiliations

  1. Laboratory of Bioactive Research and Development (LIDeB), Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata (UNLP), La Plata, Buenos Aires, Argentina

    Alan Talevi

  2. Quality Control of Pharmaceutical Products, Pharmaceutical Toxicology, Department of Biological Sciences, Faculty of Exact Sciences, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina

    Pablo A. M. Quiroga

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Graveno, M., Stratford, R.E. (2018). Absorption, Distribution, Metabolism, and Excretion of Biopharmaceutical Drug Products. In: Talevi, A., Quiroga, P. (eds) ADME Processes in Pharmaceutical Sciences. Springer, Cham. https://doi.org/10.1007/978-3-319-99593-9_11

Download citation

Publish with us

Policies and ethics

Search

Navigation