We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Open Drawer MenuClose Drawer Menu
Bioanalysis
BioTechniques
Future Drug Discovery
Future Medicinal Chemistry
Future Science OA
International Journal of Pharmacokinetics
Pharmaceutical Patent Analyst
Therapeutic Delivery
Review

Peptide therapeutics: it’s all in the delivery

    Marshall Grant

    MannKind Corporation, Danbury, CT 06810, USA

    Search for more papers by this author

    &
    Andrea Leone-Bay

    * Author for correspondence

    MannKind Corporation, Danbury, CT 06810, USA.

    Search for more papers by this author

    Email the corresponding author at aleone-bay@mannkindcorp.com

    Published Online:23 Aug 2012https://doi.org/10.4155/tde.12.79

    Abstract

    Recent work has demonstrated that the route of administration affects the pharmacokinetics and biological activity of peptides. For example, the physiological profile of insulin consists of basal and prandial components with a small-scale oscillatory element. Insulin is used more efficiently when the pharmacokinetic profile mimics features of physiological release. Noninvasive administration of insulin by oral, transdermal, nasal and pulmonary routes resembles the relatively sharp peak and short duration of exposure of prandial release. The route of administration per se, can affect the response by avoiding first-pass metabolism or perhaps altering the timing in which the peptide reaches different sets of receptors. GLP-1 delivered by injection and inhalation produces different side effect profiles. Nonclinical studies on two potential treatments for obesity, oxyntomodulin and PYY 3-36, are also presented to illustrate the relationship between exposure and effect as functions of route of administration.

    References

    • 1  Klerman EB, Adler GK, Jin M, Maliszewski AM, Brown EN. A statistical model of diurnal variation in human growth hormone. Am. J. Physiol. Endocrinol. Metab.285(5),E1118–E1126 (2003).
      Medline CASGoogle Scholar
    • 2  Hindmarsh PC. The impact of hormone physiology on clinical practice with reference to two papers spanning 40 years of endocrinology. Arch. Dis. Child.90(11),1144–1147 (2005).
      Medline CASGoogle Scholar
    • 3  Frolik CA, Black EC, Cain RL et al. Anabolic and catabolic bone effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone33(3),372–379 (2003).
      Medline CASGoogle Scholar
    • 4  Basu A, Man CD, Basu R, Toffolo G, Cobelli C, Rizza RA. Effects of Type 2 diabetes on insulin secretion, insulin action, glucose effectiveness, and postprandial glucose metabolism. Diabetes Care32(5),866–872 (2009).
      Medline CASGoogle Scholar
    • 5  Rave K, Bott S, Heinemann L et al. Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care28(5),1077–1082 (2005).
      Medline CASGoogle Scholar
    • 6  Bolli GB, Luzio S, Marzotti S et al. Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with Type 2 diabetes. Diabetes Obes. Metab.13(3),251–257 (2011).
      Medline CASGoogle Scholar
    • 7  Steiner S, Hompesch M, Pohl R et al. A novel insulin formulation with a more rapid onset of action. Diabetologia51(9),1602–1606 (2008).
      Medline CASGoogle Scholar
    • 8  Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G. First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in Type 2 diabetic subjects after bariatric surgery. Diabetes Care32(3),375–380 (2009).
      Medline CASGoogle Scholar
    • 9  Lefèbvre PJ, Paolisso G, Scheen AJ, Henquin JC. Pulsatility of insulin and glucagon release: physiological significance and pharmacological implications. Diabetologia30(7),443–452 (1987).
      Medline CASGoogle Scholar
    • 10  Ihlo CA, Lauritzen T, Sturist J, Skyggebjerg O, Christiansen JS, Larsen T. Treatment pharmacokinetics and pharmacodynamics of different modes of insulin pump delivery. A randomized, controlled study comparing subcutaneous and intravenous administration of insulin aspart. Diabetic Med.28(2),230–236 (2011).
      Medline CASGoogle Scholar
    • 11  Wasan KM. The role of lymphatic transport in enhancing oral protein and peptide drug delivery. Drug Dev. Ind. Pharm.28(9),1047–1058 (2002).
      Medline CASGoogle Scholar
    • 12  Mahato RI Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Crit. Rev. Ther. Drug Carrier Syst.20(2–3),153–214 (2003).
      Medline CASGoogle Scholar
    • 13  Hamman JH, Enslin GM, Kotze AF. Oral delivery of peptide drugs. Biodrugs19(3),165–177 (2005).
      Medline CASGoogle Scholar
    • 14  Aungst BJ. Intestinal permeation enhancers. J. Pharm. Sci.89(4),429–442 (2000).
      Medline CASGoogle Scholar
    • 15  Sharma P, Varma MVS, Chawla HPS, Panchagnula R. Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers. Il Farmaco60(11–12),884–893 (2005).
      Medline CASGoogle Scholar
    • 16  Mehta N, Erickson K, Stern W et al. nighttime dosing with an oral calcitonin tablet significantly reduces plasma CTx-1. J. Bone Miner. Res.24(Suppl. 1), (2009).
      Google Scholar
    • 17  Binkley N, Bolognese M, Sidorowicz-Bialynicka A et al. A Phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the ORACAL trial. J. Bone Miner. Res. doi:10.1002/jbmr.1602 (2012) (In Press).
      Google Scholar
    • 18  Karsdal MA, Byrjalsen I, Riis BJ, Christiansen C. Investigation of the diurnal variation in bone resorption for optimal drug delivery and efficacy in osteroporosis with oral calcitonin. BMC Clin. Pharmacol.8(12), (2008).
      Google Scholar
    • 19  Karsdal MA, Byrjalsen I, Azira M et al. Influence of food intake on the bioavailability and efficacy of oral calcitonin. Br. J. Clin. Pharmacol.67(4),413–420 (2009).
      Medline CASGoogle Scholar
    • 20  Karsdal MA, Byrjalsen I, Riis BJ, Christiansen C. Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: the effect of water and timing of meal intake on oral delivery of salmon calcitonin. BMC Clin. Pharmacol.8(5), (2008).
      Google Scholar
    • 21  Kapitza C, Zijlstra E, Heinemann L, Castelli MC, Riley G, Heise T. Oral insulin: a comparison with subcutaneous regular human insulin in patients with Type 2 diabetes. Diabetes Care33(6),1288–1290 (2010).
      Medline CASGoogle Scholar
    • 22  Clement S, Dandona P, Still JG, Kosutic G. Oral modified insulin (HIM2) in patients with Type 1 diabetes mellitus: results from a phase I/II clinical trial. Metabolism53(1),54–58 (2004).
      Medline CASGoogle Scholar
    • 23  Khedkar A, Iyer H, Anand A et al. A dose range finding study of novel oral insulin (IN-105) under fed conditions in Type 2 diabetes mellitus subjects. Diabetes Obes. Metab.12(8),659–664 (2010).
      Medline CASGoogle Scholar
    • 24  Goodman MP. Are all estrogens created equal? A review of oral vs. transdermal therapy. J. Womens Health21(2),161–169 (2012).
      Google Scholar
    • 25  Kalluri H, Banga AK. Transdermal delivery of proteins. AAPS PharmSciTech12(1),431–441 (2011).
      Medline CASGoogle Scholar
    • 26  Prausnitz MR, Langer R. Transdermal drug delivery. Nat. Biotechnol.26(11),1261–1268 (2008).
      Medline CASGoogle Scholar
    • 27  Patel YR. Altea Therapeutics Transdermal PassPort™ system: freedom from insulin injections for superior diabetes management. In: Drug Delivery in Diabetes: Making Effective Treatment Tolerable. Furness G (Ed.). ONdrugDelivery Ltd, Newtimber, UK, 4–7 (2006).
      Google Scholar
    • 28  Shalom SI, Kenan Y, Matsumoto T, Neer R. Repetitive rapid delivery of pharmacologically-active hPTH 1–34 across human skin without injection. Presented at: 30th ASMBR Annual Meeting. Montreal, Canada, 12–16 September 2008.
      Google Scholar
    • 29  Daddona PE, Matriano JA, Mandema J, Maa Y-F. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharm. Res.28(1),159–165 (2011).
      Medline CASGoogle Scholar
    • 30  Jadhav KR, Gambhire MN, Shaikh I, Kadam V, Pisal SS. Nasal drug delivery system – factors affecting and applications. Curr. Drug Ther.2(1),27–38 (2007).
      CASGoogle Scholar
    • 31  Pires A, Fortuna A, Alves G, Falcão A. Intranasal drug delivery: how, why and what for? J. Pharm. Pharmaceut. Sci.12(3),288–311 (2009).
      Medline CASGoogle Scholar
    • 32  Henkin RI. Intranasal insulin: from nose to brain. Nutrition26(6),624–633 (2010).
      Medline CASGoogle Scholar
    • 33  Ozsoy Y, Gungor S, Cevher E. Nasal delivery of high molecular weight drugs. Molecules14,3754–3779 (2009).
      Medline CASGoogle Scholar
    • 34  Leary AC, Stote RM, Cussen K, O’Brien J, Leary WP, Buckley B. Pharmacokinetics and pharmacodynamics of intranasal insulin administered to patients with Type 1 diabetes: a preliminary study. Diabetes Technol. Ther.8(1),81–88 (2006).
      Medline CASGoogle Scholar
    • 35  Leary AC, Dowling M, Cussen K, O’Brien J, Stote RM. Pharmacokinetics and pharmacodynamics of intranasal insulin spray (Nasulin™) administered to healthy male volunteers: influence of the nasal cycle. J. Diabetes Sci. Technol.2(6),1054–1060 (2008).
      MedlineGoogle Scholar
    • 36  Henkin RI. Inhaled insulin – intrapulmonary, intranasal, and other routes of administration: mechanisms of action. Nutrition26(1),33–39 (2010).
      Medline CASGoogle Scholar
    • 37  Grim M, Carlson BM. Alkaline phosphatase and dipeptidyldipeptidase IV staining of tissue components of skeletal muscle: a comparative study. J. Histochem. Cytochem.38(12),1907–1912 (1990).
      Medline CASGoogle Scholar
    • 38  Ryan JW. Peptidase enzymes of the pulmonary vascular surface. Am. J. Physiol. Lung Cell Mol. Biol.257(2),L53–L60 (1989).
      Medline CASGoogle Scholar
    • 39  Cefalu WT. Concept, strategies, and feasibility of noninvasive insulin delivery. Diabetes Care27(1),239–246 (2004).
      MedlineGoogle Scholar
    • 40  Siekmeier R, Scheuch G. Systematic treatment by inhalation of macromolecules – principles, problems, and examples. J. Physiol. Pharmacol.59(Suppl. 6),53–79 (2008).
      MedlineGoogle Scholar
    • 41  Rave K, Heise T, Pfützner A, Boss AH. Coverage of postprandial blood glucose excursions with inhaled Technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with Type 2 diabetes. Diabetes Care30(9),2307–2308 (2007).
      Medline CASGoogle Scholar
    • 42  Rave K, Heise T, Heinemann L, Boss AH. Inhaled Technosphere insulin in comparison to subcutaneous regular human insulin: time action profile and variability in subjects with Type 2 diabetes. J. Diabetes Sci. Technol.2(2),205–212 (2008).
      MedlineGoogle Scholar
    • 43  Heinemann L, Heise T. Current status of the development of inhaled insulin. Br. J. Diabetes Vasc. Dis.4(5),295–301 (2004).
      CASGoogle Scholar
    • 44  Bergenstal RM, Kapsner PL, Rendell MS et al. Comparative efficacy and safety of AFRESA™ and a rapid-acting analog both given with glargine in subjects with T1DM in a 52-week study. Presented at: American Diabetes Association’s 69th Scientific Sessions. New Orleans, LA, USA, 5–7 June 2009.
      Google Scholar
    • 45  Lorber D, Howard CP, Ren H, Rossiter A, Boss AH. Reduced incidence and frequency of hypoglycemia in an integrated analysis from clinical trials of subjects with Type 2 diabetes using prandial inhaled Technosphere® insulin. Presented at: AACE 19th Annual Meeting and Clinical Congress. Boston, MA, USA, 21–25 April 2010.
      Google Scholar
    • 46  Raskin P, Phillips MD, Rossiter A, Boss AH, Richardson PC. A1C and hypoglycemia in patients with Type 2 diabetes mellitus incorporating prandial inhaled Technosphere insulin into their usual antihyperglycemic regimen vs continuing their usual antihyperglycemic regimen. Presented at: American Diabetes Association’s 70th Scientific Sessions. Orlando, FL, USA, 25–29 June 2010.
      Google Scholar
    • 47  Rosenstock J, Lorber DL, Gnudi L et al. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for Type 2 diabetes: a multicentre randomised trial. Lancet375(9733),2244–2253 (2010).
      Medline CASGoogle Scholar
    • 48  Comulada AL, Renard E, Nakano M et al. Efficacy and safety of AIR inhaled insulin compared to insulin lispro in patients with Type 1 diabetes mellitus in a 6-month, randomized, noninferiority trial. Diabetes Technol. Ther.11(Suppl. 2),S17–S25 (2009).
      Medline CASGoogle Scholar
    • 49  Garg SK, Mathieu C, Rais N et al. Two-year efficacy and safety of AIR inhaled insulin in patients with Type 1 diabetes: an open-label randomized controlled trial. Diabetes Technol. Ther.11(Suppl. 2),S5–S16 (2009).
      Medline CASGoogle Scholar
    • 50  Hollander PA, Krasner A, Klioze S, Schwartz P, Duggan W. Body weight changes associated with insulin therapy. Diabetes Care30(10),2508–2510 (2007).
      Medline CASGoogle Scholar
    • 51  Moses RG, Bartley P, Lunt H et al. Treatment safety and efficacy of inhaled insulin (AERx iDMS1) compared with subcutaneous insulin therapy in patients with Type 1 diabetes: 1-year data from a randomized, parallel group trial. Diabetic Med.26(3),260–267 (2009).
      Medline CASGoogle Scholar
    • 52  D’Alessio DA, Vahl TP. Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. Am. J. Physiol. Endocrinol. Metab.286(6),E882–E890 (2004).
      MedlineGoogle Scholar
    • 53  Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in Type 2 diabetes: a parallel-group study. Lancet359(9309),824–830 (2002).
      Medline CASGoogle Scholar
    • 54  Vilsbøll T, Agersø H, Krarup T, Holst. JJ. Similar elimination rates of glucagon-like peptide-1 in obese Type 2 diabetic patients and healthy subjects. J. Clin. Endocrinol. Metab.88(1),220–224 (2003).
      Medline CASGoogle Scholar
    • 55  Vrang N, Larsen PJ. Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: role of peripherally secreted and centrally produced peptides. Prog. Neurobiol.92(3),442–462 (2010).
      Medline CASGoogle Scholar
    • 56  Leone-Bay A, Grant M, Greene S et al. Evaluation of novel particles as an inhalation system for GLP-1. Diabetes Obes. Metab.11(11),1050–1059 (2009).
      Medline CASGoogle Scholar
    • 57  Marino MT, Costello D, Baughman R et al. Pharmacokinetics and pharmacodynamics of inhaled GLP-1 (MKC253): proof of concept studies in healthy normal volunteers and in patients with Type 2 diabetes. Clin. Pharmacol. Ther.88(2),243–250 (2010).
      Medline CASGoogle Scholar
    • 58  Vilsbøll T, Toft-Nielsen M-B, Krarup T, Madsbad S, Dinesen B, Hulst JJ. Evaluation of b-cell secretory capacity using glucagon-like peptide-1. Diabetes Care23(6),807–812 (2000).
      Medline CASGoogle Scholar
    • 59  Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J. Nuclear Med.48(5),736–743 (2007).
      Medline CASGoogle Scholar
    • 60  Steinert RE, Poller B, Castelli MC, Drewe J, Beglinger C. Oral administration of glucagon-like peptide 1 or peptide YY 3–36 affects food intake in healthy males. Am. J. Clin. Nutr.92(4),810–817 (2010).
      Medline CASGoogle Scholar
    • 61  Beglinger C, Poller B, Arbit E et al. Pharmacokinetics and pharmacodynamic effects of oral GLP-1 and PYY3–36: a proof-of-concept study in healthy subjects. Clin. Pharmacol. Ther.84(4),469–474 (2008).
      Google Scholar
    • 62  Leone-Bay A. Mimicking endogenous peptide secretion by inhalation. Presented at: 21st American Peptide Symposium ‘Peptides: Breaking Away’. Bloomington, IN, USA, 7–12 June 2009.
      Google Scholar
    • 63  Leone-Bay A, Baughman R, Smutney C, Kocinsky J. Innovation in drug delivery by inhalation. In: Orally Inhaled and Nasal Drug Delivery: Innovations from Major Delivery System Developers. Furness G (Ed.). ONdrugDelivery Ltd, Newtimber, UK, 4–8 (2010).
      Google Scholar
    • 101  Tarsa advances OSTORA NDA filing through $28M Series B financing. www.news-medical.net/news/20120317/Tarsa-advances-OSTORA-NDA-filing-through-2428M-Series-B-financing.aspx
      Google Scholar
    • 102  Palmer A. Oppenheimer 22nd Annual Healthcare Conference. www.unigene.com/wp-content/uploads/2011/11/UniGene_1.pdf
      Google Scholar
    • 103  Atlanta Business Chronicle. $60M later, biotech Altea calls it quits. www.bizjournals.com/atlanta/print-edition/2011/12/09/60m-later-biotech-altea-calls-it-quits.html?s=print
      Google Scholar
    • 104  ClinincalTrials.gov. A study to evaluate the effect of nasal insulin on postprandial glycemic control in Type 2 diabetic patients. http://clinicaltrials.gov/ct2/show/NCT00624767
      Google Scholar
    • 105  ClinincalTrials.gov. A study of nasal PYY3–36 and placebo for weight loss in obese subjects. http://clinicaltrials.gov/ct2/show/NCT00537420
      Google Scholar
    • 106  ClinincalTrials.gov. Study to evaluate effect of intranasal teriparatide on bone mineral density in postmenopausal women with low BMD. http://clinicaltrials.gov/ct2/show/NCT00624481
      Google Scholar
    • 107  New Hampshire Business Review. CPEX drops Nasulin development. www.nhbr.com/businessnews/statenews/704288–257/cpex-drops-nasulin-development.html
      Google Scholar