Pharmacokinetics and Pharmacodynamics of Insulin Tregopil in Relation to Premeal Dosing Time, Between Meal Interval, and Meal Composition in Patients With Type 2 Diabetes Mellitus

Anand Khedkar, Harold Lebovitz, Alexander Fleming, Alan Cherrington, Vinu Jose, Sandeep N Athalye, Ashwini Vishweswaramurthy, Anand Khedkar, Harold Lebovitz, Alexander Fleming, Alan Cherrington, Vinu Jose, Sandeep N Athalye, Ashwini Vishweswaramurthy

Abstract

We evaluated the pharmacokinetics and pharmacodynamics of oral insulin tregopil in relation to premeal dosing time, between-meal interval, and meal composition type in type 2 diabetes mellitus patients in a randomized, placebo-controlled, crossover study consisting of 3 sequential cohorts. In Cohort 1, insulin tregopil administered 10 to 20 minutes before a meal resulted in optimal postmeal exposure and demonstrated better postprandial glucose-lowering effect (glucose area under concentration-time curve [AUC]) compared to the 30-minute group. In Cohort 2, insulin tregopil pharmacokinetic exposure (plasma AUC) showed a progressive increase through 4, 5, and 6 hours of between-meal interval. The 6-hour between-meal interval resulted in better absorption of insulin tregopil in comparison to 4- and 5-hour intervals. However, no significant differences were observed in pharmacodynamic parameters except for higher glucose AUC0-180min in the insulin tregopil 4-hour group during the afternoon meal as compared to the morning meal. In Cohort 3, a high-fiber meal had the least impact on insulin tregopil absorption and resulted in the highest reduction in plasma glucose levels in the afternoon. A high-fat meal reduced insulin tregopil absorption in the afternoon meal; however, pharmacodynamic response was not diminished significantly. Insulin tregopil has a rapid onset of action of approximately 10 minutes and, when administered 10 to 20 minutes before a meal, demonstrated up to 13% to 18% reduction in blood glucose levels compared to baseline. A 5-hour between-meal interval minimizes the impact of a meal on absorption of subsequent (afternoon) insulin tregopil dose, and the pharmacodynamic response of insulin tregopil is not altered by meal composition. Insulin tregopil was well tolerated in patients with type 2 diabetes mellitus.

Trial registration: ClinicalTrials.gov NCT03392961.

Keywords: food intake; insulin delivery; oral insulin; postprandial; rapid-acting insulin; type 2 diabetes mellitus.

© 2019 Biocon Limited. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Cohort 1: (A) Peripheral plasma insulin tregopil levels when administered 10, 20, and 30 minutes before meal. (B) Baseline corrected plasma glucose concentration as ratio of postmeal glucose and baseline glucose.
Figure 2
Figure 2
Cohort 2: (A) Mean plasma insulin tregopil concentration following the afternoon insulin tregopil administration at 4, 5, and 6 hours after the morning insulin tregopil and meal. (B) Baseline corrected postprandial glucose excursion, morning meal. (C) Baseline corrected postprandial glucose excursion, afternoon meal.
Figure 3
Figure 3
Cohort 3: (A) Mean insulin tregopil plasma concentrations over time for ADA meal–ADA meal. (B) Mean insulin tregopil plasma concentrations over time for high‐fat meal–ADA meal. (C) Mean insulin tregopil plasma concentrations over time for high‐fiber meal–ADA meal. (D) Baseline corrected postprandial glucose excursion, morning meal. Cohort 3: (E) Baseline corrected postprandial glucose excursion, afternoon meal.
Figure 3
Figure 3
Cohort 3: (A) Mean insulin tregopil plasma concentrations over time for ADA meal–ADA meal. (B) Mean insulin tregopil plasma concentrations over time for high‐fat meal–ADA meal. (C) Mean insulin tregopil plasma concentrations over time for high‐fiber meal–ADA meal. (D) Baseline corrected postprandial glucose excursion, morning meal. Cohort 3: (E) Baseline corrected postprandial glucose excursion, afternoon meal.
Figure 3
Figure 3
Cohort 3: (A) Mean insulin tregopil plasma concentrations over time for ADA meal–ADA meal. (B) Mean insulin tregopil plasma concentrations over time for high‐fat meal–ADA meal. (C) Mean insulin tregopil plasma concentrations over time for high‐fiber meal–ADA meal. (D) Baseline corrected postprandial glucose excursion, morning meal. Cohort 3: (E) Baseline corrected postprandial glucose excursion, afternoon meal.

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