Skip to main content
Book cover

Pharmaceutical Biotechnology pp 105–137Cite as

Pharmacokinetics and Pharmacodynamics of Therapeutic Peptides and Proteins

Abstract

The rational use of drugs and the design of effective dosage regimens are facilitated by the appreciation of the central paradigm of clinical pharmacology that there is a defined relationship between the administered dose of a drug, the resulting drug concentrations in various body fluids and tissues, and the intensity of pharmacologic effects caused by these concentrations. This dose-exposure-response relationship and thus the dose of a drug required to achieve a certain effect are determined by the drug’s pharmacokinetic and pharmacodynamic properties. The understanding of the dose-concentration-effect relationship is crucial to any drug—including peptides and proteins—as it lays the foundation for dosing regimen design and rational clinical application. General pharmacokinetic and pharmacodynamic principles are to a large extent equally applicable to protein and peptide drugs as they are to traditional small molecule-based therapeutics. Deviations from some of these principles and additional challenges with regard to the characterization of the pharmacokinetics and pharmacodynamics of therapeutic peptides and proteins, however, arise from some of their specific properties. This chapter will highlight some of the major pharmacokinetic properties and processes relevant for the majority of therapeutic peptides and proteins and will provide examples of well-characterized pharmacodynamic relationships for protein drugs.

Keywords

  • Pharmacokinetics
  • Pharmacodynamics
  • Therapeutic proteins
  • Monoclonal antibodies
  • Immunogenicity
  • PKPD-modeling
  • Pharmacometrics
  • Drug development

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-030-00710-2_6
  • Chapter length: 33 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   89.00
Price excludes VAT (USA)
  • ISBN: 978-3-030-00710-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   119.99
Price excludes VAT (USA)
Learn about institutional subscriptions
Figure 6.1
Figure 6.2
Figure 6.3
Figure 6.4
Figure 6.5
Figure 6.6
Figure 6.7
Figure 6.8
Figure 6.9
Figure 6.10
Figure 6.11
Figure 6.12
Figure 6.13
Figure 6.14
Figure 6.15
Figure 6.16
Figure 6.17
Figure 6.18
Figure 6.19
Figure 6.20
Figure 6.21
Figure 6.22
Figure 6.23

References

  • Agoram B, Heatherington AC, Gastonguay MR (2006) Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy. AAPS J 8(3):E552–E563

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Albitar M, Do KA, Johnson MM et al (2004) Free circulating soluble CD52 as a tumor marker in chronic lymphocytic leukemia and its implication in therapy with anti-CD52 antibodies. Cancer 101(5):999–1008

    CAS  PubMed  CrossRef  Google Scholar 

  • Allon M, Kleinman K, Walczyk M et al (2002) Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients undergoing dialysis. Clin Pharmacol Ther 72(5):546–555

    CAS  CrossRef  Google Scholar 

  • Anderson PM, Sorenson MA (1994) Effects of route and formulation on clinical pharmacokinetics of interleukin-2. Clin Pharmacokinet 27(1):19–31

    CAS  PubMed  CrossRef  Google Scholar 

  • Bauer RJ, Gibbons JA, Bell DP, Luo ZP, Young JD (1994) Nonlinear pharmacokinetics of recombinant human macrophage colony-stimulating factor (M-CSF) in rats. J Pharmacol Exp Ther 268(1):152–158

    CAS  PubMed  Google Scholar 

  • Baxter LT, Zhu H, Mackensen DG, Jain RK (1994) Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Res 54(6):1517–1528

    CAS  PubMed  Google Scholar 

  • Benincosa LJ, Chow FS, Tobia LP et al (2000) Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys. J Pharmacol Exp Ther 292(2):810–816

    CAS  PubMed  Google Scholar 

  • Bennett HP, McMartin C (1978) Peptide hormones and their analogues: distribution, clearance from the circulation, and inactivation in vivo. Pharmacol Rev 30(3):247–292

    CAS  PubMed  Google Scholar 

  • Berdeja J, Jagannath S, Zonder J, Badros A, Kaufman JL, Manges R, Gupta M, Tendolkar A, Lynch M, Bleickardt E, Paliwal P, Vij R (2016) Pharmacokinetics and safety of elotuzumab combined with lenalidomide and dexamethasone in patients with multiple myeloma and various levels of renal impairment: results of a phase Ib study. Clin Lymphoma Myeloma Leuk 16(3):129–138

    PubMed  CrossRef  Google Scholar 

  • Boxenbaum H (1982) Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J Pharmacokinet Biopharm 10(2):201–227

    CAS  PubMed  CrossRef  Google Scholar 

  • Bressolle F, Audran M, Gareau R, Pham TN, Gomeni R (1997) Comparison of a direct and indirect population pharmacodynamic model: application to recombinant human erythropoietin in athletes. J Pharmacokinet Biopharm 25(3):263–275

    CAS  PubMed  CrossRef  Google Scholar 

  • Bruin G, Loesche C, Nyirady J, Sander O (2017) Population pharmacokinetic modeling of secukinumab in patients with moderate to severe psoriasis. J Clin Pharmacol 57(7):876–885

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Bu G, Williams S, Strickland DK, Schwartz AL (1992) Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci U S A 89(16):7427–7431

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Caliceti P, Veronese FM (2003) Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 55(10):1261–1277

    CAS  PubMed  CrossRef  Google Scholar 

  • Carone FA, Peterson DR (1980) Hydrolysis and transport of small peptides by the proximal tubule. Am J Phys 238(3):F151–F158

    CAS  Google Scholar 

  • Carone FA, Peterson DR, Flouret G (1982) Renal tubular processing of small peptide hormones. J Lab Clin Med 100(1):1–14

    CAS  PubMed  Google Scholar 

  • Chanson P, Timsit J, Harris AG (1993) Clinical pharmacokinetics of octreotide. Therapeutic applications in patients with pituitary tumours. Clin Pharmacokinet 25(5):375–391

    CAS  PubMed  CrossRef  Google Scholar 

  • Chiang J, Gloff CA, Yoshizawa CN, Williams GJ (1993) Pharmacokinetics of recombinant human interferon-beta ser in healthy volunteers and its effect on serum neopterin. Pharm Res 10(4):567–572

    CAS  PubMed  CrossRef  Google Scholar 

  • Chirmule N, Jawa V, Meibohm B (2012) Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J 14(2):296–302

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Chow FS, Benincosa LJ, Sheth SB et al (2002) Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans. Clin Pharmacol Ther 71(4):235–245

    CAS  PubMed  CrossRef  Google Scholar 

  • Colburn W (1991) Peptide, peptoid, and protein pharmacokinetics/pharmacodynamics. In: Garzone P, Colburn W, Mokotoff M (eds) Petides, peptoids, and proteins, 3rd edn. Harvey Whitney Books, Cincinnati, pp 94–115

    Google Scholar 

  • Cumming DA (1991) Glycosylation of recombinant protein therapeutics: control and functional implications. Glycobiology 1(2):115–130

    CAS  PubMed  CrossRef  Google Scholar 

  • Daniel H, Herget M (1997) Cellular and molecular mechanisms of renal peptide transport. Am J Phys 273(1 Pt 2):F1–F8

    CAS  Google Scholar 

  • Dayneka NL, Garg V, Jusko WJ (1993) Comparison of four basic models of indirect pharmacodynamic responses. J Pharmocokinet Biopharm 21(4):457–478

    CAS  CrossRef  Google Scholar 

  • De la Peña A, Ma X, Reddy S, Ovalle F, Bergenstal RM, Jackson JA (2014) Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin. J Diabetes Sci Technol 8(4):821–829

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  • Dedrick RL (1973) Animal scale-up. J Pharmacokinet Biopharm 1(5):435–461

    CAS  PubMed  CrossRef  Google Scholar 

  • Deen WM, Lazzara MJ, Myers BD (2001) Structural determinants of glomerular permeability. Am J Physiol Renal Physiol 281(4):F579–F596

    CAS  PubMed  CrossRef  Google Scholar 

  • Deng R, Iyer S, Theil FP et al (2011) Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? MAbs 3(1):61–66

    PubMed  PubMed Central  CrossRef  Google Scholar 

  • Derendorf H, Meibohm B (1999) Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives. Pharm Res 16(2):176–185

    CAS  PubMed  CrossRef  Google Scholar 

  • Diao L, Meibohm B (2013) Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides. Clin Pharmacokinet 52(10):855–868

    CAS  PubMed  CrossRef  Google Scholar 

  • Diao L, Meibohm B (2015) Tools for predicting the PK/PD of therapeutic proteins. Expert Opin Drug Metab Toxicol 11(7):1115–1125

    CAS  PubMed  CrossRef  Google Scholar 

  • Dirks NL, Meibohm B (2010) Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49(10):633–659

    CAS  PubMed  CrossRef  Google Scholar 

  • Dong JQ, Salinger DH, Endres CJ, Gibbs JP, Hsu CP, Stouch BJ, Hurh E, Gibbs MA (2011) Quantitative prediction of human pharmacokinetics for monoclonal antibodies: retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet 50(2):131–142

    CAS  PubMed  CrossRef  Google Scholar 

  • Dugger SA, Platt A, Goldstein DB (2018) Drug development in the era of precision medicine. Nat Rev Drug Discov 17(3):183–196

    CAS  PubMed  CrossRef  Google Scholar 

  • Edwards A, Daniels BS, Deen WM (1999) Ultrastructural model for size selectivity in glomerular filtration. Am J Phys 276(6 Pt 2):F892–F902

    CAS  Google Scholar 

  • Eigenmann MJ, Fronton L, Grimm HP, Otteneder MB, Krippendorff BF (2017) Quantification of IgG monoclonal antibody clearance in tissues. MAbs 9(6):1007–1015

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Eppler SM, Combs DL, Henry TD et al (2002) A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther 72(1):20–32

    CAS  PubMed  CrossRef  Google Scholar 

  • Fasano A (1998) Novel approaches for oral delivery of macromolecules. J Pharm Sci 87(11):1351–1356

    CAS  PubMed  CrossRef  Google Scholar 

  • Flessner MF, Lofthouse J, el Zakaria R (1997) In vivo diffusion of immunoglobulin G in muscle: effects of binding, solute exclusion, and lymphatic removal. Am J Phys 273(6 Pt 2):H2783–H2793

    CAS  Google Scholar 

  • Glassman PM, Balthasar JP (2016) Physiologically-based pharmacokinetic modeling to predict the clinical pharmacokinetics of monoclonal antibodies. J Pharmacokinet Pharmacodyn 43(4):427–446

    PubMed  CrossRef  Google Scholar 

  • Glund S, Gan G, Moschetti V, Reilly P, Honickel M, Grottke O, Van Ryn J (2018) The renal elimination pathways of the dabigatran reversal agent idarucizumab and its impact on dabigatran elimination. Clin Appl Thromb Hemost 24(5):724–733

    CAS  PubMed  CrossRef  PubMed Central  Google Scholar 

  • Graham ML (2003) Pegaspargase: a review of clinical studies. Adv Drug Deliv Rev 55(10):1293–1302

    CAS  PubMed  CrossRef  Google Scholar 

  • Handelsman DJ, Swerdloff RS (1986) Pharmacokinetics of gonadotropin-releasing hormone and its analogs. Endocr Rev 7(1):95–105

    CAS  PubMed  CrossRef  Google Scholar 

  • Hayashida K, Bartlett AH, Chen Y, Park PW (2010) Molecular and cellular mechanisms of ectodomain shedding. Anat Rec 293(6):925–937

    CAS  CrossRef  Google Scholar 

  • Herbst RS, Langer CJ (2002) Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers. Semin Oncol 29(1 Suppl 4):27–36

    CAS  PubMed  CrossRef  Google Scholar 

  • Holford NH, Sheiner LB (1982) Kinetics of pharmacologic response. Pharmacol Ther 16(2):143–166

    CAS  PubMed  CrossRef  Google Scholar 

  • Inui K, Terada T, Masuda S, Saito H (2000) Physiological and pharmacological implications of peptide transporters, PEPT1 and PEPT2. Nephrol Dial Transplant 15(Suppl 6):11–13

    CAS  PubMed  CrossRef  Google Scholar 

  • Ismair MG, Stieger B, Cattori V et al (2001) Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology 121(5):1185–1190

    CAS  PubMed  CrossRef  Google Scholar 

  • Jin F, Krzyzanski W (2004) Pharmacokinetic model of target-mediated disposition of thrombopoietin. AAPS PharmSci 6(1):E9

    PubMed  CrossRef  Google Scholar 

  • Johnson V, Maack T (1977) Renal extraction, filtration, absorption, and catabolism of growth hormone. Am J Phys 233(3):F185–F196

    CAS  Google Scholar 

  • Kaufman JS, Reda DJ, Fye CL et al (1998) Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med 339(9):578–583

    CAS  PubMed  CrossRef  Google Scholar 

  • Khor SP, McCarthy K, DuPont M, Murray K, Timony G (2000) Pharmacokinetics, pharmacodynamics, allometry, and dose selection of rPSGL-Ig for phase I trial. J Pharmacol Exp Ther 293(2):618–624

    CAS  PubMed  Google Scholar 

  • Kim J, Hayton WL, Robinson JM, Anderson CL (2007) Kinetics of FcRn-mediated recycling of IgG and albumin in human: pathophysiology and therapeutic implications using a simplified mechanism-based model. Clin Immunol 122(2):146–155

    CAS  PubMed  CrossRef  Google Scholar 

  • Kingwell K (2016) Drug delivery: new targets for drug delivery across the BBB. Nat Rev Drug Discov 15(2):84–85

    CAS  PubMed  CrossRef  Google Scholar 

  • Kobayashi H, Shirakawa K, Kawamoto S et al (2002) Rapid accumulation and internalization of radiolabeled herceptin in an inflammatory breast cancer xenograft with vasculogenic mimicry predicted by the contrast-enhanced dynamic MRI with the macromolecular contrast agent G6-(1B4M-Gd)(256). Cancer Res 62(3):860–866

    CAS  PubMed  Google Scholar 

  • Kompella U, Lee V (1991) Pharmacokinetics of peptide and protein drugs. In: Lee V (ed) Peptide and protein drug delivery. Marcel Dekker, New York, pp 391–484

    Google Scholar 

  • Kontermann R (2012) Therapeutic proteins: strategies to modulate their plasma half-lives. Wiley, Weinheim

    CrossRef  Google Scholar 

  • Krogsgaard Thomsen M, Friis C, Sehested Hansen B et al (1994) Studies on the renal kinetics of growth hormone (GH) and on the GH receptor and related effects in animals. J Pediatr Endocrinol 7(2):93–105

    CAS  PubMed  CrossRef  Google Scholar 

  • Kuwabara T, Uchimura T, Kobayashi H, Kobayashi S, Sugiyama Y (1995) Receptor-mediated clearance of G-CSF derivative nartograstim in bone marrow of rats. Am J Phys 269(1 Pt 1):E1–E9

    CAS  Google Scholar 

  • Lee HJ (2002) Protein drug oral delivery: the recent progress. Arch Pharm Res 25(5):572–584

    CAS  PubMed  CrossRef  Google Scholar 

  • Lee H, Kimko HC, Rogge M et al (2003) Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis. Clin Pharmacol Ther 73(4):348–365

    CAS  PubMed  CrossRef  Google Scholar 

  • Lesko LJ (2007) Paving the critical path: how can clinical pharmacology help achieve the vision? Clin Pharmacol Ther 81(2):170–177

    CAS  PubMed  CrossRef  Google Scholar 

  • Lesko LJ, Rowland M, Peck CC, Blaschke TF (2000) Optimizing the science of drug development: opportunities for better candidate selection and accelerated evaluation in humans. J Clin Pharmacol 40(8):803–814

    CAS  PubMed  CrossRef  Google Scholar 

  • Levy G (1986) Kinetics of drug action: an overview. J Allergy Clin Immunol 78(4 Pt 2):754–761

    CAS  PubMed  CrossRef  Google Scholar 

  • Levy G (1994) Mechanism-based pharmacodynamic modeling. Clin Pharmacol Ther 56(4):356–358

    CAS  PubMed  CrossRef  Google Scholar 

  • Limothai W, Meibohm B (2011) Effect of dose on the apparent bioavailability of therapeutic proteins that undergo target-mediated drug disposition. AAPS J 13(S2)

    Google Scholar 

  • Maack T, Park C, Camargo M (1985) Renal filtration, transport and metabolism of proteins. In: Seldin D, Giebisch G (eds) The kidney. Raven Press, New York, pp 1773–1803

    Google Scholar 

  • Mach H, Gregory SM, Mackiewicz A et al (2011) Electrostatic interactions of monoclonal antibodies with subcutaneous tissue. Ther Deliv 2(6):727–736

    CAS  PubMed  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  • Mager DE, Wyska E, Jusko WJ (2003) Diversity of mechanism-based pharmacodynamic models. Drug Metab Dispos 31(5):510–518

    CAS  PubMed  CrossRef  Google Scholar 

  • Mahato RI, Narang AS, Thoma L, Miller DD (2003) Emerging trends in oral delivery of peptide and protein drugs. Crit Rev Ther Drug Carrier Syst 20(2-3):153–214

    CAS  PubMed  CrossRef  Google Scholar 

  • McMahon HT, Boucrot E (2011) Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol 12(8):517–533

    CAS  PubMed  CrossRef  Google Scholar 

  • McMartin C (1992) Pharmacokinetics of peptides and proteins: opportunities and challenges. Adv Drug Res 22:39–106

    CAS  CrossRef  Google Scholar 

  • Meibohm B (2004) Pharmacokinetics of protein- and nucleotide-based drugs. In: Mahato RI (ed) Biomaterials for delivery and targeting of proteins and nucleic acids. CRC Press, Boca Raton, pp 275–294

    Google Scholar 

  • Meibohm B, Derendorf H (1997) Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling. Int J Clin Pharmacol Ther 35(10):401–413

    CAS  PubMed  Google Scholar 

  • Meibohm B, Derendorf H (2002) Pharmacokinetic/pharmacodynamic studies in drug product development. J Pharm Sci 91(1):18–31

    CAS  PubMed  CrossRef  Google Scholar 

  • Meibohm B, Derendorf H (2004) Pharmacokinetics and pharmacodynamics of biotech drugs. In: Kayser O, Muller R (eds) Pharmaceutical biotechnology: drug discovery and clinical applications. Wiley, Weinheim, pp 147–172

    Google Scholar 

  • Meibohm B, Zhou H (2012) Characterizing the impact of renal impairment on the clinical pharmacology of biologics. J Clin Pharmacol 52(1 Suppl):54S–62S

    PubMed  CrossRef  Google Scholar 

  • Meijer D, Ziegler K (1993) Biological barriers to protein delivery. Plenum Press, New York

    Google Scholar 

  • Mohler M, Cook J, Lewis D et al (1993) Altered pharmacokinetics of recombinant human deoxyribonuclease in rats due to the presence of a binding protein. Drug Metab Dispos 21(1):71–75

    CAS  PubMed  Google Scholar 

  • Molineux G (2003) Pegylation: engineering improved biopharmaceuticals for oncology. Pharmacotherapy 23(8 Pt 2):3S–8S

    CAS  PubMed  CrossRef  Google Scholar 

  • Montero-Julian FA, Klein B, Gautherot E, Brailly H (1995) Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies. Blood 85(4):917–924

    CAS  PubMed  Google Scholar 

  • Mordenti J, Chen SA, Moore JA, Ferraiolo BL, Green JD (1991) Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm Res 8(11):1351–1359

    CAS  PubMed  CrossRef  Google Scholar 

  • Mould DR, Davis CB, Minthorn EA et al (1999) A population pharmacokinetic-pharmacodynamic analysis of single doses of clenoliximab in patients with rheumatoid arthritis. Clin Pharmacol Ther 66(3):246–257

    CAS  PubMed  CrossRef  Google Scholar 

  • Mould DR, Meibohm B (2016) Drug development of therapeutic monoclonal antibodies. BioDrugs 30(4):275–293

    CAS  PubMed  CrossRef  Google Scholar 

  • Nagaraja NV, Pechstein B, Erb K et al (2000) Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women. Clin Pharmacol Ther 68(6):617–625

    CAS  PubMed  CrossRef  Google Scholar 

  • Nagaraja NV, Pechstein B, Erb K et al (2003) Pharmacokinetic/pharmacodynamic modeling of luteinizing hormone (LH) suppression and LH surge delay by cetrorelix after single and multiple doses in healthy premenopausal women. J Clin Pharmacol 43(3):243–251

    CAS  PubMed  CrossRef  Google Scholar 

  • Nielsen S, Nielsen JT, Christensen EI (1987) Luminal and basolateral uptake of insulin in isolated, perfused, proximal tubules. Am J Phys 253(5 Pt 2):F857–F867

    CAS  Google Scholar 

  • Pauletti GM, Gangwar S, Siahaan TJ, Jeffrey A, Borchardt RT (1997) Improvement of oral peptide bioavailability: peptidomimetics and prodrug strategies. Adv Drug Deliv Rev 27(2-3):235–256

    PubMed  CrossRef  Google Scholar 

  • Pechstein B, Nagaraja NV, Hermann R et al (2000) Pharmacokinetic-pharmacodynamic modeling of testosterone and luteinizing hormone suppression by cetrorelix in healthy volunteers. J Clin Pharmacol 40(3):266–274

    CAS  PubMed  CrossRef  Google Scholar 

  • Peck CC, Barr WH, Benet LZ et al (1994) Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. J Clin Pharmacol 34(2):111–119

    CAS  PubMed  CrossRef  Google Scholar 

  • Perez-Ruixo JJ, Kimko HC, Chow AT et al (2005) Population cell life span models for effects of drugs following indirect mechanisms of action. J Pharmacokinet Pharmacodyn 32(5-6):767–793

    PubMed  CrossRef  Google Scholar 

  • Periti P, Mazzei T, Mini E (2002) Clinical pharmacokinetics of depot leuprorelin. Clin Pharmacokinet 41(7):485–504

    CAS  PubMed  CrossRef  Google Scholar 

  • Perrier D, Mayersohn M (1982) Noncompartmental determination of the steady-state volume of distribution for any mode of administration. J Pharm Sci 71(3):372–373

    CAS  PubMed  CrossRef  Google Scholar 

  • Piscitelli SC, Reiss WG, Figg WD, Petros WP (1997) Pharmacokinetic studies with recombinant cytokines. Scientific issues and practical considerations. Clin Pharmacokinet 32(5):368–381

    CAS  PubMed  CrossRef  Google Scholar 

  • Porter CJ, Charman SA (2000) Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci 89(3):297–310

    CAS  PubMed  CrossRef  Google Scholar 

  • Rabkin R, Ryan MP, Duckworth WC (1984) The renal metabolism of insulin. Diabetologia 27(3):351–357

    CAS  PubMed  CrossRef  Google Scholar 

  • Racine-Poon A, Botta L, Chang TW et al (1997) Efficacy, pharmacodynamics, and pharmacokinetics of CGP 51901, an anti-immunoglobulin E chimeric monoclonal antibody, in patients with seasonal allergic rhinitis. Clin Pharmacol Ther 62(6):675–690

    CAS  PubMed  CrossRef  Google Scholar 

  • Radwanski E, Chakraborty A, Van Wart S et al (1998) Pharmacokinetics and leukocyte responses of recombinant human interleukin-10. Pharm Res 15(12):1895–1901

    CAS  PubMed  CrossRef  Google Scholar 

  • Ramakrishnan R, Cheung WK, Wacholtz MC, Minton N, Jusko WJ (2004) Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers. J Clin Pharmacol 44(9):991–1002

    CAS  PubMed  CrossRef  Google Scholar 

  • Reddy ST, Berk DA, Jain RK, Swartz MA (2006) A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles. J Appl Physiol 101(4):1162–1169

    CAS  PubMed  CrossRef  Google Scholar 

  • Richter WF, Bhansali SG, Morris ME (2012) Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J 14(3):559–570

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Richter WF, Gallati H, Schiller CD (1999) Animal pharmacokinetics of the tumor necrosis factor receptor-immunoglobulin fusion protein lenercept and their extrapolation to humans. Drug Metab Dispos 27(1):21–25

    CAS  PubMed  Google Scholar 

  • Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7(9):715–725

    CAS  PubMed  CrossRef  Google Scholar 

  • Roskos LK, Lum P, Lockbaum P, Schwab G, Yang BB (2006) Pharmacokinetic/pharmacodynamic modeling of pegfilgrastim in healthy subjects. J Clin Pharmacol 46(7):747–757

    CAS  PubMed  CrossRef  Google Scholar 

  • Ryman JT, Meibohm B (2017) Pharmacokinetics of monoclonal antibodies. CPT: Pharmacometrics Syst Pharmacol 6(9):576–588

    CAS  Google Scholar 

  • Schomburg A, Kirchner H, Atzpodien J (1993) Renal, metabolic, and hemodynamic side-effects of interleukin-2 and/or interferon alpha: evidence of a risk/benefit advantage of subcutaneous therapy. J Cancer Res Clin Oncol 119(12):745–755

    CAS  PubMed  CrossRef  Google Scholar 

  • Sharma A, Jusko W (1998) Characteristics of indirect pharmacodynamic models and applications to clinical drug responses. Br J Clin Pharmacol 45:229–239

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979) Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 25(3):358–371

    CAS  PubMed  CrossRef  Google Scholar 

  • Sheiner LB, Steimer JL (2000) Pharmacokinetic/pharmacodynamic modeling in drug development. Annu Rev Pharmacol Toxicol 40:67–95

    CAS  PubMed  CrossRef  Google Scholar 

  • Shen WC (2003) Oral peptide and protein delivery: unfulfilled promises? Drug Discov Today 8(14):607–608

    PubMed  CrossRef  Google Scholar 

  • Smedsrod B, Einarsson M (1990) Clearance of tissue plasminogen activator by mannose and galactose receptors in the liver. Thromb Haemost 63(1):60–66

    CAS  PubMed  CrossRef  Google Scholar 

  • Straughn AB (1982) Model-independent steady-state volume of distribution. J Pharm Sci 71(5):597–598

    CAS  PubMed  CrossRef  Google Scholar 

  • Straughn AB (2006) Limitations of noncompartmental pharmacokinetic analysis of biotech drugs. In: Meibohm B (ed) Pharmacokinetics and pharmacodynamics of biotech drugs. Wiley, Weinheim, pp 181–188

    CrossRef  Google Scholar 

  • Strickland DK, Kounnas MZ, Argraves WS (1995) LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. FASEB J 9(10):890–898

    CAS  PubMed  CrossRef  Google Scholar 

  • Sun YN, Jusko WJ (1999) Role of baseline parameters in determining indirect pharmacodynamic responses. J Pharm Sci 88(10):987–990

    CAS  PubMed  CrossRef  Google Scholar 

  • Sun YN, Lee HJ, Almon RR, Jusko WJ (1999) A pharmacokinetic/pharmacodynamic model for recombinant human growth hormone effects on induction of insulin-like growth factor I in monkeys. J Pharmacol Exp Ther 289(3):1523–1532

    CAS  PubMed  Google Scholar 

  • Supersaxo A, Hein W, Gallati H, Steffen H (1988) Recombinant human interferon alpha-2a: delivery to lymphoid tissue by selected modes of application. Pharm Res 5(8):472–476

    CAS  PubMed  CrossRef  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(2):167–169

    CAS  PubMed  CrossRef  Google Scholar 

  • Suryawanshi S, Zhang L, Pfister M, Meibohm B (2010) The current role of model-based drug development. Expert Opin Drug Discovery 5(4):311–321

    CAS  CrossRef  Google Scholar 

  • Tabrizi M, Roskos LK (2006) Exposure-response relationships for therapeutic biologics. In: Meibohm B (ed) Pharmacokinetics and pharmacodynamics of biotech drugs. Wiley, Weinheim, pp 295–330

    CrossRef  Google Scholar 

  • Takagi A, Masuda H, Takakura Y, Hashida M (1995) Disposition characteristics of recombinant human interleukin-11 after a bolus intravenous administration in mice. J Pharmacol Exp Ther 275(2):537–543

    CAS  PubMed  Google Scholar 

  • Taki Y, Sakane T, Nadai T et al (1998) First-pass metabolism of peptide drugs in rat perfused liver. J Pharm Pharmacol 50(9):1013–1018

    CAS  PubMed  CrossRef  Google Scholar 

  • Tang L, Meibohm B (2006) Pharmacokinetics of peptides and proteins. In: Meibohm B (ed) Pharmacokinetics and pharmacodynamics of biotech drugs. Wiley, Weinheim, pp 17–44

    Google Scholar 

  • Tang L, Persky AM, Hochhaus G, Meibohm B (2004) Pharmacokinetic aspects of biotechnology products. J Pharm Sci 93(9):2184–2204

    CAS  PubMed  CrossRef  Google Scholar 

  • Tanswell P, Modi N, Combs D, Danays T (2002) Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet 41(15):1229–1245

    CAS  PubMed  CrossRef  Google Scholar 

  • Tokuda Y, Watanabe T, Omuro Y et al (1999) Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. Br J Cancer 81(8):1419–1425

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Toon S (1996) The relevance of pharmacokinetics in the development of biotechnology products. Eur J Drug Metab Pharmacokinet 21(2):93–103

    CAS  PubMed  CrossRef  Google Scholar 

  • Veng-Pedersen P, Gillespie W (1984) Mean residence time in peripheral tissue: a linear disposition parameter useful for evaluating a drug’s tissue distribution. J Pharmacokinet Biopharm 12(5):535–543

    CAS  PubMed  CrossRef  Google Scholar 

  • Veronese FM, Caliceti P (2006) Custom-tailored pharmacokinetics and pharmacodynamics via chemical modifications of biotech drugs. In: Meibohm B (ed) Pharmacokinetics and pharmacodynamics of boptech drugs. Wiley, Weinheim, pp 271–294

    CrossRef  Google Scholar 

  • Walsh S, Shah A, Mond J (2003) Improved pharmacokinetics and reduced antibody reactivity of lysostaphin conjugated to polyethylene glycol. Antimicrob Agents Chemother 47(2):554–558

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Wang W, Wang EQ, Balthasar JP (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84(5):548–558

    CAS  PubMed  CrossRef  Google Scholar 

  • Wills RJ, Ferraiolo BL (1992) The role of pharmacokinetics in the development of biotechnologically derived agents. Clin Pharmacokinet 23(6):406–414

    CAS  PubMed  CrossRef  Google Scholar 

  • Yang BB (2006) Integration of pharmacokinetics and pharmacodynamics into the drug development of pegfilgrastim, a pegylated protein. In: Meibohm B (ed) Pharmacokinetics and pharmacodynamics of biotech drugs. Wiley, Weinheim, pp 373–394

    CrossRef  Google Scholar 

  • Zamboni WC (2003) Pharmacokinetics of pegfilgrastim. Pharmacotherapy 23(8 Pt 2):9S–14S

    CAS  PubMed  CrossRef  Google Scholar 

  • Zhang Y, Meibohm B (2012) Pharmacokinetics and pharmacodynamics and therapeutic peptides and proteins. In: Kayzer O, Warzecha H (eds) Pharmaceutical biotechnology: drug discovery and clinical applications. Wiley, Weinheim, pp 337–368

    CrossRef  Google Scholar 

  • Zhang L, Pfister M, Meibohm B (2008) Concepts and challenges in quantitative pharmacology and model-based drug development. AAPS J 10(4):552–559

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Zhao L, Ji P, Li Z, Roy P, Sahajwalla CG (2013) The antibody drug absorption following subcutaneous or intramuscular administration and its mathematical description by coupling physiologically based absorption process with the conventional compartment pharmacokinetic model. J Clin Pharmacol 53(3):314–325

    CAS  PubMed  CrossRef  Google Scholar 

  • Zia-Amirhosseini P, Minthorn E, Benincosa LJ et al (1999) Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys. J Pharmacol Exp Ther 291(3):1060–1067

    CAS  PubMed  Google Scholar 

  • Ziegler K, Polzin G, Frimmer M (1988) Hepatocellular uptake of cyclosporin A by simple diffusion. Biochim Biophys Acta 938(1):44–50

    CAS  PubMed  CrossRef  Google Scholar 

  • Zito SW (1997) Pharmaceutical biotechnology: a programmed text. Technomic, Lancaster

    Google Scholar 

Further Reading

    General Pharmacokinetics and Pharmacodynamics

    • Atkinson A, Abernethy D, Daniels C, Dedrick R, Markey S (2006) Principles of clinical pharmacology. Academic, San Diego

      Google Scholar 

    • Bonate PL (2011) Pharmacokinetic-pharmacodynamic modeling and simulation. Springer, New York

      CrossRef  Google Scholar 

    • Derendorf H, Meibohm B (1999) Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives. Pharm Res 16(2):176–185

      CAS  PubMed  CrossRef  Google Scholar 

    • Gabrielsson J, Hjorth S (2012) Quantitative pharmacology. Swedish Academy of Pharmaceutical Sciences, Stockholm

      Google Scholar 

    • Gibaldi M, Perrier D (1982) Pharmacokinetics. Marcel Dekker, New York

      Google Scholar 

    • Holford NH, Sheiner LB (1982) Kinetics of pharmacologic response. Pharmacol Ther 16(2):143–166

      CAS  PubMed  CrossRef  Google Scholar 

    • Rowland M, Tozer TN (2011) Clinical pharmacokinetics and pharmacodynamics: concepts and applications. Lippincott Williams & Wilkins, Baltimore

      Google Scholar 

    Pharmacokinetics and Pharmacodynamics of Peptides and Proteins

    • Diao L, Meibohm B (2013) Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides. Clin Pharmacokinet 52(10):855–868

      CAS  PubMed  CrossRef  Google Scholar 

    • Diao L, Meibohm B (2015) Tools for predicting the PK/PD of therapeutic proteins. Expert Opin Drug Metab Toxicol 11(7):1115–1125

      CAS  PubMed  CrossRef  Google Scholar 

    • Kontermann R (2012) Therapeutic proteins: strategies to modulate their plasma half-lives. Wiley, Weinheim

      CrossRef  Google Scholar 

    • Meibohm B (2006) Pharmacokinetics and pharmacodynamics of biotech drugs. Wiley, Weinheim

      CrossRef  Google Scholar 

    • Mould DR, Meibohm B (2016) Drug development of therapeutic monoclonal antibodies. BioDrugs 30(4):275–293

      CAS  PubMed  CrossRef  Google Scholar 

    • Ryman JT, Meibohm B (2017) Pharmacokinetics of monoclonal antibodies. CPT: Pharmacometrics Syst Pharmacol 6(9):576–588

      CAS  Google Scholar 

    • Tang L, Persky AM, Hochhaus G, Meibohm B (2004) Pharmacokinetic aspects of biotechnology products. J Pharm Sci 93(9):2184–2204

      CAS  PubMed  CrossRef  Google Scholar 

    Download references

    Author information

    Authors and Affiliations

    1. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Pharmacy, Memphis, TN, USA

      Bernd Meibohm

    Authors
    1. Bernd Meibohm
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Bernd Meibohm .

    Editor information

    Editors and Affiliations

    1. Utrecht University, Utrecht, The Netherlands

      Daan J. A. Crommelin

    2. Faculty of Pharmaceutical Sciences and The Centre for Health Evaluation & Outcomes Sciences (CHEOS), The University of British Columbia (UBC), Vancouver, BC, Canada

      Dr. Robert D. Sindelar

    3. College of Pharmacy, University of Tennessee, Health Science Center, Memphis, TN, USA

      Bernd Meibohm

    Rights and permissions

    Reprints and Permissions

    Copyright information

    © 2019 Springer Nature Switzerland AG

    About this chapter

    Verify currency and authenticity via CrossMark

    Cite this chapter

    Meibohm, B. (2019). Pharmacokinetics and Pharmacodynamics of Therapeutic Peptides and Proteins. In: Crommelin, D., Sindelar, R., Meibohm, B. (eds) Pharmaceutical Biotechnology. Springer, Cham. https://doi.org/10.1007/978-3-030-00710-2_6

    Download citation