Pharmacokinetic and Pharmacodynamic Characteristics of Insulin Icodec After Subcutaneous Administration in the Thigh, Abdomen or Upper Arm in Individuals with Type 2 Diabetes Mellitus

Leona Plum-Mörschel, Lizette Ravn Andersen, Solvejg Hansen, Ulrike Hövelmann, Patricia Krawietz, Niels Rode Kristensen, Lars Lang Lehrskov, Hanne Haahr, Leona Plum-Mörschel, Lizette Ravn Andersen, Solvejg Hansen, Ulrike Hövelmann, Patricia Krawietz, Niels Rode Kristensen, Lars Lang Lehrskov, Hanne Haahr

Abstract

Background and objective: Individuals with diabetes mellitus may prefer different body regions for subcutaneous insulin administration. This trial investigated whether choice of injection region affects exposure and glucose-lowering effect of once-weekly basal insulin icodec.

Methods: In a randomised, open-label, crossover trial, 25 individuals with type 2 diabetes received single subcutaneous icodec injections (5.6 U/kg) in the thigh, abdomen or upper arm (9-13 weeks' washout). Pharmacokinetic blood sampling occurred frequently until 35 days post-dose. Partial glucose-lowering effect was assessed 36-60 h post-dose in a glucose clamp (target 7.5 mmol/L). Steady-state pharmacokinetics following multiple once-weekly dosing were simulated using a two-compartment pharmacokinetic model.

Results: Total icodec exposure (area under the curve from zero to infinity after single dose; AUC0-∞,SD) was similar between injection in the thigh, abdomen and upper arm (estimated AUC0-∞,SD ratios [95% confidence interval]: abdomen/thigh 1.02 [0.96-1.09], p = 0.473; upper arm/thigh 1.04 [0.98-1.10], p = 0.162; abdomen/upper arm 0.98 [0.93-1.05], p = 0.610). Maximum icodec concentration (Cmax) after single dose was higher for abdomen (by 17%, p = 0.002) and upper arm (by 24%, p < 0.001) versus thigh. When simulated to steady state, smaller differences in Cmax were seen for abdomen (by 11%, p = 0.004) and upper arm (by 16%, p < 0.001) versus thigh. Geometric mean [coefficient of variation] glucose-lowering effect 36-60 h post-dose was comparable between the thigh (1961 mg/kg [51%]), abdomen (2130 mg/kg [52%]) and upper arm (2391 mg/kg [40%]).

Conclusion: Icodec can be administered subcutaneously in the thigh, abdomen or upper arm with no clinically relevant difference in exposure and with a similar glucose-lowering effect.

Gov identifier: NCT04582448.

Conflict of interest statement

Leona Plum-Mörschel received travel grants and/or speaker fees from Eli Lilly, Gan & Lee Pharmaceuticals and Novo Nordisk. Solvejg Hansen is an employee of Novo Nordisk. Lizette Ravn Andersen, Niels Rode Kristensen, Lars Lang Lehrskov and Hanne Haahr are employees and shareholders of Novo Nordisk. Ulrike Hövelmann and Patricia Krawietz declare that they have no conflict of interest.

© 2023. The Author(s).

Figures

Fig. 1
Fig. 1
Overall trial design. Individuals participated in three 5-week periods, each consisting of single-dose subcutaneous administration of insulin icodec in the thigh, abdomen or upper arm in randomised sequence. Single dose injections were separated by 9–13 weeks of washout PK pharmacokinetic
Fig. 2
Fig. 2
Mean (SEM) serum insulin icodec concentration-time profiles during a dosing interval of 1 week following subcutaneous injection of insulin icodec (5.6 U/kg) in the thigh, abdomen or upper arm. a After a single dose. b Simulated to once-weekly administration at steady state using pharmacokinetic modelling. Data are based on 23 individual pharmacokinetic profiles for thigh and upper arm and 24 individual pharmacokinetic profiles for abdomen. Error bands show standard error of the mean
Fig. 3
Fig. 3
Comparison of insulin icodec exposure among subcutaneous injection regions. Total exposure (AUC0–∞,SD) and maximum concentration (Cmax,SD) were derived after a single dose of insulin icodec (5.6 U/kg). Cmax,SS was derived after simulation to once-weekly administration at steady state. Results for AUC0–∞,SD also reflect total exposure at steady state (AUCτ,SS) because extrapolation to steady state has no effect on total exposure. Data are based on 23 individual pharmacokinetic profiles for thigh and upper arm and 24 individual pharmacokinetic profiles for abdomen. AUC0–∞ area under the curve from 0 to infinity, AUCτ area under the curve during a dosing interval, CI confidence interval, Cmax maximum concentration, SD single dose, SS steady state
Fig. 4
Fig. 4
Mean (SEM) glucose-lowering effect profiles from 36 to 60 h following a single dose of insulin icodec (5.6 U/kg) injected subcutaneously in the thigh, abdomen or upper arm. Data are based on 22 individual glucose-lowering effect profiles for thigh and upper arm and 23 individual glucose-lowering effect profiles for abdomen. Error bands show standard error of the mean

References

    1. Frid AH, Hirsch LJ, Menchior AR, et al. Worldwide Injection Technique Questionnaire study: population parameters and injection practices. Mayo Clin Proc. 2016;91:1212–1223. doi: 10.1016/j.mayocp.2016.06.011.
    1. Frid AH, Kreugel G, Grassi G, et al. New insulin delivery recommendations. Mayo Clin Proc. 2016;91:1231–1255. doi: 10.1016/j.mayocp.2016.06.010.
    1. De Coninck C, Frid A, Gaspar R, et al. Results and analysis of the 2008–2009 Insulin Injection Technique Questionnaire survey. J Diabetes. 2010;2:168–179. doi: 10.1111/j.1753-0407.2010.00077.x.
    1. Bantle JP, Neal L, Frankamp LM. Effects of the anatomical region used for insulin injections on glycemia in type I diabetes subjects. Diabetes Care. 1993;16:1592–1597. doi: 10.2337/diacare.16.12.1592.
    1. ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 1996;19:1437–1440. doi: 10.2337/diacare.19.12.1437.
    1. Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 1999;22:1501–1506. doi: 10.2337/diacare.22.9.1501.
    1. Hövelmann U, Heise T, Nosek L, et al. Pharmacokinetic properties of fast-acting insulin aspart administered in different subcutaneous injection regions. Clin Drug Investig. 2017;37:503–509. doi: 10.1007/s40261-017-0499-y.
    1. Kjeldsen TB, Hubálek F, Hjørringgaard CU, et al. Molecular engineering of insulin icodec, the first acylated insulin analog for once-weekly administration in humans. J Med Chem. 2021;64:8942–8950. doi: 10.1021/acs.jmedchem.1c00257.
    1. Nishimura E, Pridal L, Glendorf T, et al. Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once-weekly dosing. BMJ Open Diabetes Res Care. 2021;9:e002301. doi: 10.1136/bmjdrc-2021-002301.
    1. Rosenstock J, Bajaj HS, Janež A, et al. Once-weekly insulin for type 2 diabetes without previous insulin treatment. N Engl J Med. 2020;383:2107–2116. doi: 10.1056/NEJMoa2022474.
    1. Bajaj HS, Bergenstal RM, Christoffersen A, et al. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in type 2 diabetes inadequately controlled on daily basal insulin: a phase 2 randomized controlled trial. Diabetes Care. 2021;44:1586–1594. doi: 10.2337/dc20-2877.
    1. Lingvay I, Buse JB, Franek E, et al. A randomized, open-label comparison of once-weekly insulin icodec titration strategies versus once-daily insulin glargine U100. Diabetes Care. 2021;44:1595–1603. doi: 10.2337/dc20-2878.
    1. Benesch C, Heise T, Klein O, Heinemann L, Arnolds S. How to assess the quality of glucose clamps? Evaluation of clamps performed with ClampArt, a novel automated clamp device. J Diabetes Sci Technol. 2015;9:792–800. doi: 10.1177/1932296815576957.
    1. American Diabetes Association Professional Practice Committee 6. Glycemic targets: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(Suppl 1):S83–S96. doi: 10.2337/dc22-S006.
    1. Nosek L, Coester H-V, Roepstorff C, et al. Glucose-lowering effect of insulin degludec is independent of subcutaneous injection region. Clin Drug Investig. 2014;34:673–679. doi: 10.1007/s40261-014-0218-x.
    1. Morello CM. Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus. Int J Gen Med. 2011;4:827–835. doi: 10.2147/IJGM.S26889.
    1. Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R. Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care. 2000;23:813–819. doi: 10.2337/diacare.23.6.813.
    1. Heise T, Korsatko S, Nosek L, et al. Steady state is reached within 2–3 days of once-daily administration of degludec, a basal insulin with an ultralong duration of action. J Diabetes. 2016;8:132–138. doi: 10.1111/1753-0407.12266.
    1. Brod M, Alolga SL, Meneghini L. Barriers to initiating insulin in type 2 diabetes patients: development of a new patient education tool to address myths, misconceptions and clinical realities. Patient. 2014;7:437–450. doi: 10.1007/s40271-014-0068-x.
    1. Ng CJ, Lai PS, Lee YK, Azmi SA, Teo CH. Barriers and facilitators to starting insulin in patients with type 2 diabetes: a systematic review. Int J Clin Pract. 2015;69:1050–1070. doi: 10.1111/ijcp.12691.

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