dose range finding study of novel oral insulin (IN-105) under fed conditions in type 2 diabetes mellitus subjects

• Published in: Diabetes, obesity & metabolism Vol. 12; no. 8; pp. 659 - 664
• Main Authors: Khedkar, A, Iyer, H, Anand, A, Verma, M, Krishnamurthy, S, Savale, S, Atignal, A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-08-2010; Blackwell Publishing Ltd; Wiley Subscription Services, Inc
• Subjects: Administration, Oral; Adult; Aged; C-Peptide - drug effects; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Dosage; Drug Administration Schedule; Female; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Insulin; Insulin - administration & dosage; Insulin - analogs & derivatives; Insulin - pharmacokinetics; Insulin secretion; Male; Metformin; Metformin - administration & dosage; Metformin - pharmacokinetics; Middle Aged; oral insulin; Peptides; pharmacodynamics; pharmacokinetics; pharmacology; Placebos; Plasma levels; Postprandial Period; Tablets; Tablets - administration & dosage; Treatment Outcome; type 2 diabets mellitus
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2010.01213.x

Aim: The objective of the study was to establish the dose response of IN-105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin. Methods: The primary objective was to examine the effect of sequential single ascending doses of IN-105 on the plasma glucose concentration under fed conditions. All subjects received, sequentially, matching placebo, 10, 15, 20 and 30 mg IN-105 tablets in five consecutive periods. Tablets were administered 20 min prior to meal in all the periods. Plasma levels of immunoreactive insulin, C-peptide and glucose were measured up to 180 min from the time of dosing. The changes in postprandial glucose levels at 120 min in response to IN-105 administration were also compared against those of placebo. Results: Changes in glucose from baseline (mean ± s.d.) at 140 min (2 h postprandial) were 94.84 ± 22.3, 79.45 ± 43.00, 70.68 ± 35.71, 63.47 ± 42.75 and 53.06 ± 47.27 mg/dL, respectively, and exhibited linear dose-response. The insulin Cmax values were found to be 50.8 ± 26.0 mU/L for placebo, 100.3 ± 66.7 with 10 mg IN-105, 177.69 ± 150.3 with 15 mg IN-105, 246.2 ± 245.2 with 20 mg IN-105 and 352.5 ± 279.3 mU/L with 30 mg of IN-105. Conclusions: IN-105 absorption is proportional to the dose administered. The 2-h postprandial glucose excursion was reduced in a dose proportional manner. Circulating C-peptide levels were found to be suppressed in proportion to the IN-105 exposure. IN-105 reduces glucose excursion despite lower endogenous insulin secretion. IN-105 seems to have a wide therapeutic window as no clinical hypoglycaemia was observed at any of the doses studied.