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Clinical Trial
. 2019 May;12(3):276-282.
doi: 10.1111/cts.12609. Epub 2019 Feb 12.

Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open-Label, Placebo-Controlled, Crossover Study

Anand Khedkar  1 , Harold Lebovitz  2 , Alexander Fleming  3 , Alan Cherrington  4 , Vinu Jose  1 , Sandeep N Athalye  1 , Ashwini Vishweswaramurthy  1
Affiliations
Clinical Trial

Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open-Label, Placebo-Controlled, Crossover Study

Anand Khedkar et al. Clin Transl Sci. 2019 May.

Abstract

Oral insulin tregopil (IN-105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN-105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study the effect of IN-105 on pharmacokinetics (PKs) of metformin. In this randomized, open-label, cross-over study, metformin was administered to healthy volunteers receiving IN-105/placebo under fed/fasting conditions. The 90% confidence interval (CI) of the geometric mean ratio of the area under the curve from time zero to infinity (AUC0-inf ; fasting and fed) and peak plasma concentration (Cmax ; fed) of metformin were within 0.80-1.25 acceptance range. Under fasting conditions, the upper bound margin of Cmax was just beyond this range (i.e., 1.27) and was concluded as functionally not relevant. There was no clinically significant effect of sodium caprate/IN-105 on PKs of metformin under fasting/fed conditions, and it was safe.

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Conflict of interest statement

Drs Anand Khedkar and Vinu Jose were employees of Biocon Research Ltd. at the time of study conduct. Dr Harold Lebovitz is a scientific advisor for Biocon, Intarcia Pharmaceuticals, Metacure Ltd., and Poxel Pharmaceuticals. He holds stocks in Abbott, AbbVie, Inc., General Electric, Gilead Sciences, Inc., IBM, Nestlé, and Novartis AG. Dr Alan D. Cherrington is a scientific advisor for Biocon, Fractyl Laboratories, Inc., Metavention, and NuSirt Biopharma, Inc., Sensulin Labs, LLC., These Three Medical, Inc. (T3M), VTV Therapeutics, and Zafgen. He is a consultant at Abvance, Boston Scientific Corporation, California Institute for Biomedical Research (Calibr), Eli Lilly and Company, Galvani Bioelectronics Limited, MedImmune, Novo Nordisk Inc., Silver Lake, Thermalin Diabetes, LLC., Thetis Pharmaceuticals LLC., and VTV Therapeutics. He has received research support from Boston Scientific Corporation, Galvani Bioelectronics Limited, Novo Nordisk, Inc., Silver Lake, and Zafgen, and holds stocks in Fractyl Laboratories, Inc., Metavention, Thetis Pharmaceuticals LLC., and Zafgen and has professional relationships with Abvance, Sensulin Labs, LLC. Dr Alexander Fleming is a board member of Tolerion and Innoneo. He is a consultant at Acasti, Adocia, Biocon, Cardiora, Carthera, Casebia, Diamyd, Diasome, Dance, EnteraBio, Emperra, Fractyl, G‐Medical, Immune Pharma, InsuLine Medical, Intarcia Therapeutics, Intra‐Cellular Therapeutics, InClinica, Ipsen Biopharmaceuticals, Lexicon, Mars Symbioscience, Mediwound, Merck KGaA, Mediwound, Metronom, Mylan, Neovii, NuSirt Biopharma, Orgenesis, Oramed, Permeatus, ProSciento, RenovoRx, Rhythm Pharmaceuticals, Sanofi, Serpin, SkinJect, Suzhou Connect, Thermalin, ThermoFisher, Upkara, Veracyte, VeroScience, Xeris Pharmaceuticals, and Zucara. Dr Sandeep N. Athalye is an employee of Biocon Research Limited and holds stocks in Biocon. Dr Ashwini Vishweswaramurthy is an employee of Biocon Research Limited.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Mean (± SD) plasma metformin concentrations (semilog) vs. time after oral administration in healthy volunteers by treatment in cohort 1.
Figure 3
Figure 3
Mean (± SD) plasma metformin concentrations (semilog) vs. time after oral administration in healthy volunteers by treatment in cohort 2.
Figure 4
Figure 4
Geometric mean ratio and 90% confidence interval (CI) for metformin in cohorts 1 and 2. AUC, area under the curve; AUCinf, AUC from time zero to infinity; Cmax, peak plasma concentration IN‐105, insulin tregopil.
See this image and copyright information in PMC

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