The online version of this article (https://doi.org/10.1007/s40262-019-00772-2) contains supplementary material, which is available to authorized users.
Oral insulin 338 is a novel tablet formulation of a long-acting basal insulin. This randomised, open-label, four-period crossover trial investigated the effect of timing of food intake on the single-dose pharmacokinetic properties of oral insulin 338.
After an overnight fast, 44 healthy males received single fixed doses of oral insulin 338 administered 0, 30, 60 or 360 min before consuming a standardised meal (500 kcal, 57 energy percent [E%] carbohydrate, 13 E% fat, 30 E% protein). Blood samples for pharmacokinetic assessment were taken up to 288 h post-dose.
Total exposure (area under the concentration-time curve from time zero to infinity [AUCIns338,0–∞]) and maximum concentration (Cmax,Ins338) of insulin 338 were both significantly lower for 0 versus 360 min post-dose fasting (ratio [95% confidence interval (CI)]: 0.36 [0.26–0.49], p < 0.001, and 0.35 [0.25–0.49], p < 0.001, respectively). There were no significant differences in AUCIns338,0–∞ and Cmax,Ins338 for 30 or 60 versus 360 min post-dose fasting (ratio [95% CI] 30 versus 360 min: 0.85 [0.61–1.21], p = 0.36, and 0.86 [0.59–1.26], p = 0.42; ratio [95% CI] 60 versus 360 min: 0.96 [0.72–1.28], p = 0.77, and 0.99 [0.75–1.31], p = 0.95). The mean half-life was ~ 55 h independent of the post-dose fasting period. Oral insulin 338 was well-tolerated with no safety issues identified during the trial.
Oral insulin 338 pharmacokinetics are not affected by food intake from 30 min after dosing, implying that patients with diabetes mellitus do not need to wait more than 30 min after a morning dose of oral insulin 338 before having their breakfast. This is considered important for convenience and treatment compliance.
Supplementary material 1 (PDF 1111 kb)40262_2019_772_MOESM1_ESM.pdf
Heinemann L, Jacques Y. Oral insulin and buccal insulin: a critical reappraisal. J Diabetes Sci Technol. 2009;3:568–84. CrossRef
Iyer H, Khedkar A, Verma M. Oral insulin—a review of current status. Diabetes Obes Metab. 2010;12:179–85. CrossRef
Zijlstra E, Heinemann L, Plum-Mörschel L. Oral insulin reloaded: a structured approach. J Diabetes Sci Technol. 2014;8:458–65. CrossRef
Wong CY, Martinez J, Dass CR. Oral delivery of insulin for treatment of diabetes: status quo, challenges and opportunities. J Pharm Pharmacol. 2016;68:1093–108. CrossRef
Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov. 2003;2:289–95. CrossRef
Aguirre TA, Teijeiro-Osorio D, Rosa M, Coulter IS, Alonso MJ, Brayden DJ. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv Drug Deliv Rev. 2016;106:223–41. CrossRef
Walsh EG, Adamczyk BE, Chalasani KB, Maher S, O’Toole EB, Fox JS, et al. Oral delivery of macromolecules: rationale underpinning Gastrointestinal Permeation Enhancement Technology (GIPET). Ther Deliv. 2011;2:1595–610. CrossRef
Halberg IB, Lyby K, Wassermann K, Heise T, Zijlstra E, Plum-Mörschel L. Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in subjects with type 2 diabetes: an 8-week, randomised, double-blind phase 2 trial. Lancet Diabetes Endocrinol. 2019;7:179–88. CrossRef
Maher S, Leonard TW, Jacobsen J, Brayden DJ. Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic. Adv Drug Deliv Rev. 2009;61:1427–49. CrossRef
Schmidt LE, Dalhoff K. Food–drug interactions. Drugs. 2002;62:1481–502. CrossRef
European Medicines Agency. Committee for Human Medicinal Products. Guideline on the investigation of drug interactions. 2012. https://www.ema.europa.eu/documents/scientific-guideline/guideline-investigation-drug-interactions_en.pdf. Accessed 16 Apr 2019.
U.S. Food and Drug Administration. Guidance for Industry. Food-effect bioavailability and fed bioequivalence studies. 2002. https://www.fda.gov/media/70945/download. Accessed 16 Apr 2019.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384–95. CrossRef
Eldor R, Arbit E, Miteva Y, Freier R, Kidron M. Oral insulin: type I diabetes (T1DM) patient response upon preprandial administration. Diabetes. 2010;59(Suppl 1):A141 (Abstract).
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. 2008;8:5. CrossRef
Karsdal MA, Byrjalsen I, Azria M, Arnold M, Choi L, Riis BJ, et al. Influence of food intake on the bioavailability and efficacy of oral calcitonin. Br J Clin Pharmacol. 2009;67:413–20. CrossRef
Bækdal TA, Borregaard J, Donsmark M, Breitschaft A, Søndergaard FL. Evaluation of the effects of water volume with dosing and post-dose fasting period on pharmacokinetics of oral semaglutide. Diabetes. 2017;66(Suppl 1):A315 (Abstract).
Kidron M, Dinh S, Menachem Y, Abbas R, Variano B, Goldberg M, et al. A novel per-oral insulin formulation: proof of concept study in non-diabetic subjects. Diabet Med. 2004;21:354–7. CrossRef
Heise T, Nosek L, Arbit E, et al. Reduction of postprandial blood glucose excursions by an optimized formulation of oral insulin. Diabetes. 2005;54(Suppl 1):A103 (Abstract).
Luzio SD, Dunseath G, Lockett A, Broke-Smith TP, New RR, Owens DR. The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes. Diabetes Obes Metab. 2010;12:82–7. CrossRef
Khedkar A, Iyer H, Anand A, Verma M, Krishnamurthy S, Savale S, 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. 2010;12:659–64. CrossRef
Chakera AJ, Pearce SH, Vaidya B. Treatment for primary hypothyroidism: current approaches and future possibilities. Drug Des Devel Ther. 2012;6:1–11.
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 Care. 2010;33:1288–90. CrossRef
European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on the investigation of bioequivalence. 2010. https://www.ema.europa.eu/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf. Accessed 16 Apr 2019.
- The Effect of Food Intake on the Pharmacokinetics of Oral Basal Insulin: A Randomised Crossover Trial in Healthy Male Subjects
Inge B. Halberg
- Springer International Publishing
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926