Download PDF
Drug Res (Stuttg) 2016; 66(03): 113-120
DOI: 10.1055/s-0035-1559654
Review
© Georg Thieme Verlag KG Stuttgart · New York

Oral Delivery of Therapeutic Proteins and Peptides: An Overview of Current Technologies and Recommendations for Bridging from Approved Intravenous or Subcutaneous Administration to Novel Oral Regimens

M. Philippart
1   Department of Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands
,
J. Schmidt
2   F. Hoffmann-La Roche Ltd., Global Product Strategy, Product Optimization, Basel, Switzerland
,
B. Bittner
2   F. Hoffmann-La Roche Ltd., Global Product Strategy, Product Optimization, Basel, Switzerland
› Author Affiliations
Further Information

Publication History

received 17 March 2015

accepted 25 July 2015

Publication Date:
04 November 2015 (online)

Also available at
    Permissions and Reprints

Abstract

Since the early 1980s, therapeutic proteins and peptides have become established as an important class of pharmaceuticals. Due to their low oral bioavailability, which results from pre-systemic degradation and poor gastrointestinal absorption, most therapeutic proteins and peptides are administered intravenously. While subcutaneous formulations of some therapeutic proteins and peptides have been shown to improve patient convenience and reduce medical resource utilization, oral administration is generally the preferred administration route. Some therapeutic proteins and peptides employing novel oral delivery technologies have reached late-stage clinical development. To develop a new oral formulation of a therapeutic protein or peptide currently marketed as an injectable product, technical, nonclinical, and clinical studies are required to demonstrate similar safety and efficacy compared with the existing administration route. Since there is little experience with oral therapeutic proteins and peptides, this review provides recommendations for bridging from an approved intravenous or subcutaneous regimen to novel oral administration of the same therapeutic protein or peptide, based on precedents from intravenous-to-subcutaneous bridging approaches for trastuzumab, rituximab, tocilizumab, and bortezomib. If the pharmacokinetic/pharmacodynamic relationship is well characterized, demonstration of comparability in prespecified pharmacokinetic parameters might form a basis for establishing similar efficacy and safety of the oral formulation vs. the reference product. Although oral administration of therapeutic proteins and peptides remains challenging, given recent progress with novel delivery technologies, intravenous/subcutaneous-to-oral nonclinical and clinical bridging programs may soon be utilized to support approval of new oral formulations.

Key words

monoclonal antibody - pharmacokinetics - rituximab - tocilizumab - trastuzumab - bortezomib
 

  • References

  • 1 Carter PJ. Introduction to current and future protein therapeutics: a protein engineering perspective. Exp Cell Res 2011; 317: 1261-1269
    CrossrefPubMedGoogle Scholar
  • 2 Hamman JH, Enslin GM, Kotze AF. Oral delivery of peptide drugs: barriers and developments. BioDrugs 2005; 19: 165-177
    CrossrefPubMedGoogle Scholar
  • 3 Ratnaparkhi MP, Chaudhari SP, Pandya VA. Peptides and proteins in pharmaceuticals. Int J Curr Pharmaceut Res 2011; 3: 1-9
    PubMedGoogle Scholar
  • 4 Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 2008; 7: 21-39
    CrossrefPubMedGoogle Scholar
  • 5 Yun Y, Cho YW, Park K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv Drug Deliv Rev 2013; 65: 822-832
    CrossrefPubMedGoogle Scholar
  • 6 Park K, Kwon IC, Park K. Oral protein delivery: Current status and future prospect. React Funct Polym 2011; 71: 280-287
    CrossrefPubMedGoogle Scholar
  • 7 Renukuntla J, Vadlapudi AD, Patel A et al. Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 2013; 447: 75-93
    CrossrefPubMedGoogle Scholar
  • 8 Pivot X, Gligorov J, Müller V et al. PrefHer Study Group . Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. Lancet Oncol 2013; 14: 962-970
    CrossrefPubMedGoogle Scholar
  • 9 Hourcade-Potelleret F, Lemenuel-Diot A, McIntyre C et al. Use of a population pharmacokinetic approach for the clinical development of a fixed-dose subcutaneous formulation of trastuzumab. CPT Pharmacometrics Syst Pharmacol 2014; 3: e87
    CrossrefPubMedGoogle Scholar
  • 10 Burcombe R, Chan S, Simcock R et al. Subcutaneous trastuzumab (Herceptin®): A UK Time and Motion study in comparison with intravenous formulation for the treatment of patients with HER2-positive early breast cancer. Adv Breast Can Res 2013; 2: 133-140
    PubMedGoogle Scholar
  • 11 Bittner B, Richter WF, Hourcade-Potelleret F et al. Development of a subcutaneous formulation for trastuzumab – nonclinical and clinical bridging approach to the approved intravenous dosing regimen. Arzneimittelforschung 2012; 62: 401-409
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Bittner B, Richter WF, Hourcade-Potelleret F et al. Non-clinical pharmacokinetic/pharmacodynamic and early clinical studies supporting development of a novel subcutaneous formulation for the monoclonal antibody rituximab. Drug Res (Stuttg) 2014; 64: 569-575
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Gupta S, Jain A, Chakraborty M et al. Oral delivery of therapeutic proteins and peptides: a review on recent developments. Drug Deliv 2013; 20: 237-246
    CrossrefPubMedGoogle Scholar
  • 14 Fasano A. Innovative strategies for the oral delivery of drugs and peptides. Trends Biotechnol 1998; 16: 152-157
    CrossrefPubMedGoogle Scholar
  • 15 Barclay N, Tarallo M, Hendrikx T et al. Patient preference for oral versus injectable and intravenous methods of treatment for rheumatoid arthritis. Poster presented at the 16th Annual European Congress of the International Society of Pharmacoeconomics and Outcomes Research (ISPOR-EU); November 2–6 2013 Dublin, Ireland
    PubMedGoogle Scholar
  • 16 Borner MM, Schoffski P, de Wit R et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002; 38: 349-358
    CrossrefPubMedGoogle Scholar
  • 17 Dibonaventura MD, Wagner JS, Girman CJ et al. Multinational Internet-based survey of patient preference for newer oral or injectable Type 2 diabetes medication. Patient Prefer Adherence 2010; 4: 397-406
    PubMedGoogle Scholar
  • 18 Melmed S, Popovic V, Bidlingmaier M et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J Clin Endocrinol Metab 2015; 100: 1699-1708
    CrossrefPubMedGoogle Scholar
  • 19 Binkley N, Bolognese M, Sidorowicz-Bialynicka A et al. Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) Investigators . A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial. J Bone Miner Res 2012; 27: 1821-1829
    CrossrefPubMedGoogle Scholar
  • 20 Lee VHL, Dodda-Kashi S, Grass GM et al. Oral route of peptide and protein drug delivery. In: Lee VHL. (ed.) Peptide and protein drug delivery. New York: Marcel Dekker; 1991: 691-738
    Google Scholar
  • 21 Werle M, Makhlof A, Takeuchi H. Oral protein delivery: a patent review of academic and industrial approaches. Recent Pat Drug Deliv Formul 2009; 3: 94-104
    CrossrefPubMedGoogle Scholar
  • 22 Woodley JF. Enzymatic barriers for GI peptide and protein delivery. Crit Rev Ther Drug Carrier Syst 1994; 11: 61-95
    PubMedGoogle Scholar
  • 23 Wacher VJ, Silverman JA, Zhang Y et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 1998; 87: 1322-1330
    CrossrefPubMedGoogle Scholar
  • 24 Toorisaka E, Ono H, Arimori K et al. Hypoglycemic effect of surfactant-coated insulin solubilized in a novel solid-in-oil-in-water (S/O/W) emulsion. Int J Pharm 2003; 252: 271-274
    CrossrefPubMedGoogle Scholar
  • 25 Niu M, Lu Y, Hovgaard L et al. Hypoglycemic activity and oral bioavailability of insulin-loaded liposomes containing bile salts in rats: the effect of cholate type, particle size and administered dose. Eur J Pharm Biopharm 2012; 81: 265-272
    CrossrefPubMedGoogle Scholar
  • 26 Lowman AM, Morishita M, Kajita M et al. Oral delivery of insulin using pH-responsive complexation gels. J Pharm Sci 1999; 88: 933-937
    CrossrefPubMedGoogle Scholar
  • 27 Liu X, Liu C, Zhang W et al. Oligoarginine-modified biodegradable nanoparticles improve the intestinal absorption of insulin. Int J Pharm 2013; 448: 159-167
    CrossrefPubMedGoogle Scholar
  • 28 Agarwal V, Nazzal S, Reddy IK et al. Transport studies of insulin across rat jejunum in the presence of chicken and duck ovomucoids. J Pharm Pharmacol 2001; 53: 1131-1138
    CrossrefPubMedGoogle Scholar
  • 29 Brinckerhoff LH, Kalashnikov VV, Thompson LW et al. Terminal modifications inhibit proteolytic degradation of an immunogenic MART-1(27–35) peptide: implications for peptide vaccines. Int J Cancer 1999; 83: 326-334
    CrossrefPubMedGoogle Scholar
  • 30 Kidron M, Dinh S, Menachem Y et al. A novel per-oral insulin formulation: proof of concept study in non-diabetic subjects. Diabet Med 2004; 21: 354-357
    CrossrefPubMedGoogle Scholar
  • 31 Bechara C, Sagan S. Cell-penetrating peptides: 20 years later, where do we stand?. FEBS Lett 2013; 587: 1693-1702
    CrossrefPubMedGoogle Scholar
  • 32 Khafagy el-S, Morishita M. Oral biodrug delivery using cell-penetrating peptide. Adv Drug Deliv Rev 2012; 64: 531-539
    CrossrefPubMedGoogle Scholar
  • 33 Traverso G, Schoellhammer CM, Schroeder A et al. Microneedles for drug delivery via the gastrointestinal tract. J Pharm Sci 2015; 104: 362-367
    CrossrefPubMedGoogle Scholar
  • 34 www.emisphere.com [accessed October 2014]
    PubMed
  • 35 Castelli MC, Wong DF, Friedman K et al. Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects. Clin Ther 2011; 33: 934-945
    CrossrefPubMedGoogle Scholar
  • 36 Lee CM, Chen CY, Chien RN et al. A double-blind randomized controlled study to evaluate the efficacy of low-dose oral interferon-alpha in preventing hepatitis C relapse. J Interferon Cytokine Res 2014; 34: 187-194
    CrossrefPubMedGoogle Scholar
  • 37 Bennett AL, Smith DW, Cummins MJ et al. Low-dose oral interferon alpha as prophylaxis against viral respiratory illness: a double-blind, parallel controlled trial during an influenza pandemic year. Influenza Other Respir Viruses 2013; 7: 854-862
    CrossrefPubMedGoogle Scholar
  • 38 http://www.bone-ltd.com [accessed October 2014]
    PubMed
  • 39 Bone Ltd. Platform Technologies
    PubMed
  • 40 http://www.merrionpharma.com [accessed October 2014]
    PubMed
  • 41 http://www.oramed.com [accessed October 2014]
    PubMed
  • 42 Eldor R, Kidron M, Arbi E. A Single-Blind, Two-Period Study to Assess the Safety and Pharmacodynamics of an Orally Delivered GLP-1 Analog (Exenatide) in Healthy Subjects. Poster presented at the 70th Scientific Sessions of the American Diabetes Association; June 25–29 2010 Orlando, FL
    PubMedGoogle Scholar
  • 43 http://enterisbiopharma.com [accessed October 2014]
    PubMed
  • 44 Henriksen K, Andersen JR, Riis BJ et al. Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis. Bone 2013; 53: 160-166
    CrossrefPubMedGoogle Scholar
  • 45 http://www.caratherapeutics.com [accessed October 2014]
    PubMed
  • 46 http://www.chiasmapharma.com [accessed October 2014]
    PubMed
  • 47 Tuvia S, Pelled D, Marom K et al. A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms. Pharm Res 2014; 31: 2010-2021
    CrossrefPubMedGoogle Scholar
  • 48 European Medicines Agency . Herceptin Summary of Product Characteristics. September 2014
    PubMedGoogle Scholar
  • 49 European Medicines Agency . MabThera Summary of Product Characteristics. July 2014
    PubMedGoogle Scholar
  • 50 European Medicines Agency . RoActemra Summary of Product Characteristics. September 2014
    PubMedGoogle Scholar
  • 51 European Medicines Agency . Velcade Summary of Product Characteristics. April 2014
    PubMedGoogle Scholar
  • 52 Ismael G, Hegg R, Muehlbauer S et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre randomised trial. Lancet Oncol 2012; 13: 869-878
    CrossrefPubMedGoogle Scholar
  • 53 Davies A, Merli F, Mihaljevic B et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol 2014; 15: 343-352
    CrossrefPubMedGoogle Scholar
  • 54 Burmester GR, Rubbert-Roth A, Cantagrel A et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014; 73: 69-74
    CrossrefPubMedGoogle Scholar
  • 55 Ogata A, Tanimura K, Sugimoto T et al. Musashi Study Investigators. Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014; 66: 344-354
    CrossrefPubMedGoogle Scholar
  • 56 Moreau P, Pylypenko H, Grosicki S et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431-440
    CrossrefPubMedGoogle Scholar
  • 57 European Medicines Agency . Assessment report: Herceptin. June 2013
    PubMedGoogle Scholar
  • 58 European Medicines Agency . Assessment report: MabThera. January 2014
    PubMedGoogle Scholar
  • 59 European Medicines Agency . Assessment report: Velcade. June 2012
    PubMedGoogle Scholar
  • 60 European Medicines Agency . Assessment report: RoActemra. February 2014
    PubMedGoogle Scholar
  • 61 Bookbinder LH, Hofer A, Haller MF et al. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Control Release 2006; 114: 230-241
    CrossrefPubMedGoogle Scholar
  • 62 Moreau P, Coiteux V, Hulin C et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 2008; 93: 1908-1911
    CrossrefPubMedGoogle Scholar
  • 63 Wynne C, Harvey V, Schwabe C et al. Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer. J Clin Pharmacol 2013; 53: 192-201
    CrossrefPubMedGoogle Scholar
  • 64 Salar A, Avivi I, Bittner B et al. 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 2014; 32: 1782-1791
    CrossrefPubMedGoogle Scholar
  • 65 Zhang X, Chen YC, Fettner S et al. Pharmacokinetics and pharmacodynamics of tocilizumab after subcutaneous administration in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther 2013; 51: 620-630
    CrossrefPubMedGoogle Scholar
  • 66 Zhang X, Georgy A, Rowell L. Pharmacokinetics and pharmacodynamics of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, following single-dose administration by subcutaneous and intravenous routes to healthy subjects. Int J Clin Pharmacol Ther 2013; 51: 443-455
    CrossrefPubMedGoogle Scholar
  • 67 http://clinicaltrials.gov/ct2/show/NCT01200758 [accessed October 2014]
    PubMed
  • 68 Ohta S, Tsuru T, Terao K et al. Mechanism-based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study). J Clin Pharmacol 2014; 54: 109-119
    CrossrefPubMedGoogle Scholar
  • 69 Morcos PN, Zhang X, McIntyre C et al. Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuPH20. Int J Clin Pharmacol Ther 2013; 51: 537-548
    CrossrefPubMedGoogle Scholar
  • 70 Kivitz A, Olech E, Borofsky M et al. Subcutaneous tocilizumab vs. placebo in combination with disease modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014; 66: 1653-1661
    CrossrefPubMedGoogle Scholar
  • 71 Liang JF, Yang VC. Insulin-cell penetrating peptide hybrids with improved intestinal absorption efficiency. Biochem Biophys Res Commun 2005; 335: 734-738
    CrossrefPubMedGoogle Scholar
  • 72 Wang DD, Zhang S, Zhao H et al. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009; 49: 1012-1024
    CrossrefPubMedGoogle Scholar
  • 73 Lui CY, Amidon GL, Berardi RR et al. Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dog as a model for oral absorption in humans. J Pharm Sci 1986; 75: 271-274
    CrossrefPubMedGoogle Scholar
  • 74 Musther H, Olivares-Morales A, Hatley OJ et al. Animal versus human oral drug bioavailability: do they correlate?. Eur J Pharm Sci 2014; 57: 280-291
    CrossrefPubMedGoogle Scholar
  • 75 Akabane T, Tabata K, Kadono K et al. A comparison of pharmacokinetics between humans and monkeys. Drug Metab Dispos 2010; 38: 308-316
    CrossrefPubMedGoogle Scholar
  • 76 Parrott N, Lukacova V, Fraczkiewicz G et al. Predicting pharmacokinetics of drugs using physiologically based modeling – application to food effects. AAPS J 2009; 11: 45-53
    CrossrefPubMedGoogle Scholar
  • 77 Stroh M, Duda DG, Takimoto CH et al. Translation of anticancer efficacy from nonclinical models to the clinic. CPT Pharmacometrics Syst Pharmacol 2014; 3: e128
    CrossrefPubMedGoogle Scholar
  • 78 Tuvia S, Atsmon J, Teichman SL et al. Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression. J Clin Endocrinol Metab 2012; 97: 2362-2369
    CrossrefPubMedGoogle Scholar
  • 79 Mao CP, Brovarney MR, Dabbagh K et al. Subcutaneous versus intravenous administration of rituximab: pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys. PLoS One 2013; 8: e80533
    CrossrefPubMedGoogle Scholar