Modeling energy intake and body weight effects of a long-acting amylin analogue

  • Annika Brings
  • Jens Markus Borghardt
  • Jolanta Skarbaliene
  • Tamara Baader-Pagler
  • Maria A. Deryabina
  • Wolfgang Rist
  • Stefan Scheuerer
Original Paper

Abstract

The inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats. EI and body weight (BW) were measured daily and LAMY concentrations in plasma were assessed using defined time points following subcutaneous administration of the LAMY at different dosing regimens. Overall, 6 pharmacodynamic (PD) studies including a total of 173 rats were considered in this evaluation. Treatment caused a dose-dependent reduction in EI and BW, although multiple dosing indicated the development of tolerance over time. This behavior could be adequately described by a population model including homeostatic feedback of EI and a turnover model describing the relationship between EI and BW. The model was evaluated by testing its ability to predict BW loss in a toxicology study and was utilized to improve the understanding of dosing regimens for obesity therapy. As such, the model proved to be a valuable tool for the design and interpretation of rodent studies used in anti-obesity drug development.

Keywords

Model-informed drug discovery Obesity Energy intake Amylin analogue Tolerance 

Notes

Acknowledgements

The authors would like to thank Hermann Rapp for valuable discussions and Dr. Arno Kalkuhl for providing us with the toxicology study data. Moreover, we like to thank Sidsel Larsen, Charlotte Holtoft, Arne Lindhardt Jensen, Jessica Bedenik and Christina Doll for excellent technical support.

Author contributions

All authors provided critical review of drafts of the manuscript, and read and approved the final version. AB and JB contributed equally to the development of the model, to the interpretation of the modeling results and writing the manuscript. All other authors contributed to the design of the study and interpretation of the data, and supported and reviewed the model compilation.

Compliance with ethical standards

Conflict of interest

Jens M. Borghardt, Wolfgang Rist, Stefan Scheuerer and Tamara Baader-Pagler are employees of Boehringer Ingelheim Pharma GmbH & Co KG. Jolanta Skarbaliene and Maria A. Deryabina are employees of Zealand Pharma A/S. Annika Brings was an employee of Boehringer Ingelheim Pharma GmbH & Co KG at the time of the manuscript creation.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

10928_2017_9557_MOESM1_ESM.pdf (230 kb)
Supplementary material 1 (PDF 230 kb)
10928_2017_9557_MOESM2_ESM.pdf (205 kb)
Supplementary material 2 (PDF 205 kb)
10928_2017_9557_MOESM3_ESM.pdf (318 kb)
Supplementary material 3 (PDF 318 kb)
10928_2017_9557_MOESM4_ESM.pdf (360 kb)
Supplementary material 4 (PDF 359 kb)
10928_2017_9557_MOESM5_ESM.pdf (313 kb)
Supplementary material 5 (PDF 312 kb)
10928_2017_9557_MOESM6_ESM.pdf (230 kb)
Supplementary material 6 (PDF 230 kb)
10928_2017_9557_MOESM7_ESM.pdf (322 kb)
Supplementary material 7 (PDF 322 kb)
10928_2017_9557_MOESM8_ESM.pdf (91 kb)
Supplementary material 8 (PDF 90 kb)
10928_2017_9557_MOESM9_ESM.pdf (59 kb)
Supplementary material 9 (PDF 59 kb)

References

  1. 1.
    Fernstrom JD, Choi S (2008) The development of tolerance to drugs that suppress food intake. Pharmacol Ther 117(1):105–122. https://doi.org/10.1016/j.pharmthera.2007.09.001 CrossRefPubMedGoogle Scholar
  2. 2.
    Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (2006) Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295(7):761–775. https://doi.org/10.1001/jama.295.7.761 CrossRefPubMedGoogle Scholar
  3. 3.
    Bray GA, Ryan DH, Gordon D, Heidingsfelder S, Cerise F, Wilson K (1996) A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 4(3):263–270CrossRefPubMedGoogle Scholar
  4. 4.
    James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF (2000) Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine trial of obesity reduction and maintenance. Lancet 356(9248):2119–2125CrossRefPubMedGoogle Scholar
  5. 5.
    Wirth A, Krause J (2001) Long-term weight loss with sibutramine: a randomized controlled trial. JAMA 286(11):1331–1339CrossRefPubMedGoogle Scholar
  6. 6.
    Weintraub M (1992) Long-term weight control: The National Heart, Lung, and Blood Institute funded multimodal intervention study. Clin Pharmacol Ther 51(5):581–585CrossRefPubMedGoogle Scholar
  7. 7.
    Ravussin E, Smith SR, Mitchell JA, Shringarpure R, Shan K, Maier H, Koda JE, Weyer C (2009) Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 17(9):1736–1743. https://doi.org/10.1038/oby.2009.184 CrossRefGoogle Scholar
  8. 8.
    Smith SR, Aronne LJ, Burns CM, Kesty NC, Halseth AE, Weyer C (2008) Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care 31(9):1816–1823. https://doi.org/10.2337/dc08-0029 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD (2008) Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci USA 105(20):7257–7262. https://doi.org/10.1073/pnas.0706473105 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Fisas A, Codony X, Romero G, Dordal A, Giraldo J, Merce R, Holenz J, Vrang N, Sorensen RV, Heal D, Buschmann H, Pauwels PJ (2006) Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats. Br J Pharmacol 148(7):973–983. https://doi.org/10.1038/sj.bjp.0706807 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Madsen AN, Hansen G, Paulsen SJ, Lykkegaard K, Tang-Christensen M, Hansen HS, Levin BE, Larsen PJ, Knudsen LB, Fosgerau K, Vrang N (2010) Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. J Endocrinol 206(3):287–296. https://doi.org/10.1677/JOE-10-0004 CrossRefPubMedGoogle Scholar
  12. 12.
    Choi S, Jonak EM, Simpson L, Patil V, Fernstrom JD (2002) Intermittent, chronic fenfluramine administration to rats repeatedly suppresses food intake despite substantial brain serotonin reductions. Brain Res 928(1–2):30–39CrossRefPubMedGoogle Scholar
  13. 13.
    Seeley RJ, Burklow ML, Wilmer KA, Matthews CC, Reizes O, McOsker CC, Trokhan DP, Gross MC, Sheldon RJ (2005) The effect of the melanocortin agonist, MT-II, on the defended level of body adiposity. Endocrinology 146(9):3732–3738. https://doi.org/10.1210/en.2004-1663 CrossRefPubMedGoogle Scholar
  14. 14.
    Sahu A (2002) Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones. J Neuroendocrinol 14(10):796–804CrossRefPubMedGoogle Scholar
  15. 15.
    Roth JD, Hughes H, Kendall E, Baron AD, Anderson CM (2006) Antiobesity effects of the beta-cell hormone amylin in diet-induced obese rats: effects on food intake, body weight, composition, energy expenditure, and gene expression. Endocrinology 147(12):5855–5864. https://doi.org/10.1210/en.2006-0393 CrossRefPubMedGoogle Scholar
  16. 16.
    Mack C, Wilson J, Athanacio J, Reynolds J, Laugero K, Guss S, Vu C, Roth J, Parkes D (2007) Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight. Am J Physiol Regul Integr Comp Physiol 293(5):R1855–R1863. https://doi.org/10.1152/ajpregu.00297.2007 CrossRefPubMedGoogle Scholar
  17. 17.
    Roth JD, Hughes H, Coffey T, Maier H, Trevaskis JL, Anderson CM (2007) Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat-fed female rats. Am J Physiol Endocrinol Metab 293(4):E1112–E1117. https://doi.org/10.1152/ajpendo.00395.2007 CrossRefPubMedGoogle Scholar
  18. 18.
    Donahey JC, van Dijk G, Woods SC, Seeley RJ (1998) Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats. Brain Res 779(1–2):75–83CrossRefPubMedGoogle Scholar
  19. 19.
    Larsen PJ, Fledelius C, Knudsen LB, Tang-Christensen M (2001) Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes 50(11):2530–2539CrossRefPubMedGoogle Scholar
  20. 20.
    Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443(7109):289–295. https://doi.org/10.1038/nature05026 CrossRefPubMedGoogle Scholar
  21. 21.
    Lutz TA (2012) Effects of amylin on eating and adiposity. Handb Exp Pharmacol 209:231–250. https://doi.org/10.1007/978-3-642-24716-3_10 CrossRefGoogle Scholar
  22. 22.
    Lutz TA (2012) Control of energy homeostasis by amylin. Cell Mol Life Sci 69(12):1947–1965. https://doi.org/10.1007/s00018-011-0905-1 CrossRefPubMedGoogle Scholar
  23. 23.
    Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD (2015) Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev 67(3):564–600. https://doi.org/10.1124/pr.115.010629 CrossRefPubMedGoogle Scholar
  24. 24.
    Roth JD, Coffey T, Jodka CM, Maier H, Athanacio JR, Mack CM, Weyer C, Parkes DG (2007) Combination therapy with amylin and peptide YY[3-36] in obese rodents: anorexigenic synergy and weight loss additivity. Endocrinology 148(12):6054–6061. https://doi.org/10.1210/en.2007-0898 CrossRefPubMedGoogle Scholar
  25. 25.
    Isaksson B, Wang F, Permert J, Olsson M, Fruin B, Herrington MK, Enochsson L, Erlanson-Albertsson C, Arnelo U (2005) Chronically administered islet amyloid polypeptide in rats serves as an adiposity inhibitor and regulates energy homeostasis. Pancreatology 5(1):29–36. https://doi.org/10.1159/000084488 CrossRefPubMedGoogle Scholar
  26. 26.
    Danhof M, Alvan G, Dahl SG, Kuhlmann J, Paintaud G (2005) Mechanism-based pharmacokinetic-pharmacodynamic modeling-a new classification of biomarkers. Pharm Res 22(9):1432–1437. https://doi.org/10.1007/s11095-005-5882-3 CrossRefPubMedGoogle Scholar
  27. 27.
    Fang J, DuBois DC, He Y, Almon RR, Jusko WJ (2011) Dynamic modeling of methylprednisolone effects on body weight and glucose regulation in rats. J Pharmacokinet Pharmacodyn 38(3):293–316. https://doi.org/10.1007/s10928-011-9194-4 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jacquier M, Crauste F, Soulage CO, Soula HA (2014) A predictive model of the dynamics of body weight and food intake in rats submitted to caloric restrictions. PLoS One 9(6):e100073. https://doi.org/10.1371/journal.pone.0100073 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Tam J, Fukumura D, Jain RK (2009) A mathematical model of murine metabolic regulation by leptin: energy balance and defense of a stable body weight. Cell Metab 9(1):52–63. https://doi.org/10.1016/j.cmet.2008.11.005 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gennemark P, Hjorth S, Gabrielsson J (2015) Modeling energy intake by adding homeostatic feedback and drug intervention. J Pharmacokinet Pharmacodyn 42(1):79–96. https://doi.org/10.1007/s10928-014-9399-4 CrossRefPubMedGoogle Scholar
  31. 31.
    Ito K, Murphy D (2013) Application of ggplot2 to pharmacometric graphics. CPT 2:e79. https://doi.org/10.1038/psp.2013.56 Google Scholar
  32. 32.
    Soetaert K, Petzoldt T, Setzer RW (2010) Solving differential equations in R: package deSolve. J Stat Softw 33(9):1–25. https://doi.org/10.1137/0915088 CrossRefGoogle Scholar
  33. 33.
    Newby FD, DiGirolamo M, Cotsonis GA, Kutner MH (1990) Model of spontaneous obesity in aging male Wistar rats. Am J Physiol 259(6 Pt 2):R1117–R1125PubMedGoogle Scholar
  34. 34.
    Hubert MF, Laroque P, Gillet JP, Keenan KP (2000) The effects of diet, ad Libitum feeding, and moderate and severe dietary restriction on body weight, survival, clinical pathology parameters, and cause of death in control Sprague-Dawley rats. Toxicol Sci 58(1):195–207CrossRefPubMedGoogle Scholar
  35. 35.
    Chow CC, Hall KD (2008) The dynamics of human body weight change. PLoS Comput Biol 4(3):e1000045. https://doi.org/10.1371/journal.pcbi.1000045 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Polidori D, Sanghvi A, Seeley RJ, Hall KD (2016) How strongly does appetite counter weight loss? Quantification of the feedback control of human energy intake. Obesity (Silver Spring) 24(11):2289–2295. https://doi.org/10.1002/oby.21653 CrossRefGoogle Scholar
  37. 37.
    Chow CC, Hall KD (2014) Short and long-term energy intake patterns and their implications for human body weight regulation. Physiol Behav 134:60–65. https://doi.org/10.1016/j.physbeh.2014.02.044 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Guo J, Hall KD (2011) Predicting changes of body weight, body fat, energy expenditure and metabolic fuel selection in C57BL/6 mice. PLoS ONE 6(1):e15961. https://doi.org/10.1371/journal.pone.0015961 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Guo J, Hall KD (2009) Estimating the continuous-time dynamics of energy and fat metabolism in mice. PLoS Comput Biol 5(9):e1000511. https://doi.org/10.1371/journal.pcbi.1000511 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gennemark P, Jansson-Lofmark R, Hyberg G, Wigstrand M, Kakol-Palm D, Hakansson P, Hovdal D, Brodin P, Fritsch-Fredin M, Antonsson M, Ploj K, Gabrielsson J (2013) A modeling approach for compounds affecting body composition. J Pharmacokinet Pharmacodyn 40(6):651–667. https://doi.org/10.1007/s10928-013-9337-x CrossRefPubMedGoogle Scholar
  41. 41.
    Selimkhanov J, Thompson WC, Patterson TA, Hadcock JR, Scott DO, Maurer TS, Musante CJ (2016) Evaluation of a mathematical model of rat body weight regulation in application to caloric restriction and drug treatment studies. PLoS ONE 11(5):e0155674. https://doi.org/10.1371/journal.pone.0155674 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Diao L, Meibohm B (2013) Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides. Clin Pharmacokinet 52(10):855–868. https://doi.org/10.1007/s40262-013-0079-0 CrossRefPubMedGoogle Scholar
  43. 43.
    Probst RJ, Lim JM, Bird DN, Pole GL, Sato AK, Claybaugh JR (2006) Gender differences in the blood volume of conscious Sprague-Dawley rats. J Am Assoc Lab Anim Sci 45(2):49–52PubMedPubMedCentralGoogle Scholar
  44. 44.
    Marques C, Meireles M, Norberto S, Leite J, Freitas J, Pestana D, Faria A, Calhau C (2016) High-fat diet-induced obesity Rat model: a comparison between Wistar and Sprague-Dawley Rat. Adipocyte 5(1):11–21. https://doi.org/10.1080/21623945.2015.1061723 CrossRefPubMedGoogle Scholar
  45. 45.
    Gong H, Han YW, Sun L, Zhang Y, Zhang EY, Li Y, Zhang TM (2016) The effects of energy intake of four different feeding patterns in rats. Exp Biol Med (Maywood) 241(1):52–59. https://doi.org/10.1177/1535370215584890 CrossRefGoogle Scholar
  46. 46.
    Owen JS, Fiedler-Kelly J (2014) Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models. Wiley, HobokenCrossRefGoogle Scholar
  47. 47.
    Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rossner S, Van Gaal L, Astrup A, Investigators NN (2014) Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond) 38(5):689–697. https://doi.org/10.1038/ijo.2013.149 CrossRefGoogle Scholar
  48. 48.
    Aronne L, Fujioka K, Aroda V, Chen K, Halseth A, Kesty NC, Burns C, Lush CW, Weyer C (2007) Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab 92(8):2977–2983. https://doi.org/10.1210/jc.2006-2003 CrossRefPubMedGoogle Scholar
  49. 49.
    Kanoski SE, Rupprecht LE, Fortin SM, De Jonghe BC, Hayes MR (2012) The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology 62(5–6):1916–1927. https://doi.org/10.1016/j.neuropharm.2011.12.022 CrossRefPubMedGoogle Scholar
  50. 50.
    Hjuler ST, Gydesen S, Andreassen KV, Pedersen SL, Hellgren LI, Karsdal MA, Henriksen K (2016) The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. Obesity (Silver Spring) 24(8):1712–1722. https://doi.org/10.1002/oby.21563 CrossRefGoogle Scholar
  51. 51.
    Friedman J (2014) 20 years of leptin: leptin at 20: an overview. J Endocrinol 223(1):T1–T8. https://doi.org/10.1530/JOE-14-0405 CrossRefPubMedGoogle Scholar
  52. 52.
    Ingwersen SH, Khurana M, Madabushi R, Watson E, Jonker DM, Le Thi TD, Jacobsen LV, Tornoe CW (2012) Dosing rationale for liraglutide in type 2 diabetes mellitus: a pharmacometric assessment. J Clin Pharmacol 52(12):1815–1823. https://doi.org/10.1177/0091270011430504 CrossRefPubMedGoogle Scholar
  53. 53.
    Overgaard RV, Petri KC, Jacobsen LV, Jensen CB (2016) Liraglutide 3.0 mg for weight management: a population pharmacokinetic analysis. Clin Pharmacokinet 55(11):1413–1422. https://doi.org/10.1007/s40262-016-0410-7 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Petri KC, Jacobsen LV, Klein DJ (2015) Comparable liraglutide pharmacokinetics in pediatric and adult populations with type 2 diabetes: a population pharmacokinetic analysis. Clin Pharmacokinet 54(6):663–670. https://doi.org/10.1007/s40262-014-0229-z CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Hall KD (2008) What is the required energy deficit per unit weight loss? Int J Obes (Lond) 32(3):573–576. https://doi.org/10.1038/sj.ijo.0803720 CrossRefGoogle Scholar
  56. 56.
    Gennemark P, Tragardh M, Linden D, Ploj K, Johansson A, Turnbull A, Carlsson B, Antonsson M (2017) Translational modeling to guide study design and dose choice in obesity exemplified by AZD1979, a melanin-concentrating hormone receptor 1 antagonist. CPT 6(7):458–468. https://doi.org/10.1002/psp4.12199 Google Scholar
  57. 57.
    Hall KD, Hammond RA, Rahmandad H (2014) Dynamic interplay among homeostatic, hedonic, and cognitive feedback circuits regulating body weight. Am J Public Health 104(7):1169–1175. https://doi.org/10.2105/AJPH.2014.301931 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co KGBiberachGermany
  2. 2.Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KGBiberachGermany
  3. 3.Zealand Pharma A/SCopenhagenDenmark

Personalised recommendations