The Effect of Food Intake on the Pharmacokinetics of Oral Basal Insulin: A Randomised Crossover Trial in Healthy Male Subjects

Inge B Halberg, Karsten Lyby, Karsten Wassermann, Tim Heise, Leona Plum-Mörschel, Eric Zijlstra, Inge B Halberg, Karsten Lyby, Karsten Wassermann, Tim Heise, Leona Plum-Mörschel, Eric Zijlstra

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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. CLINICALTRIALS.

Gov identifier: NCT02304627.

Conflict of interest statement

Inge B. Halberg, Karsten Lyby and Karsten Wassermann are employees and shareholders of Novo Nordisk. Tim Heise is a shareholder of Profil, which has received research funds from Adocia, Boehringer Ingelheim, Dance Pharmaceuticals, Eli Lilly, Johnson & Johnson, MedImmune, Merck Sharp and Dohme, Mylan, Nordic Bioscience, Novo Nordisk, Poxel, Roche Diagnostics, Saniona, Sanofi, Senseonics and Zealand Pharma. In addition, Tim Heise is member of advisory panels for Novo Nordisk and Mylan and received speaker honoraria and travel grants from Dexcom, Eli Lilly, Mylan, Novo Nordisk, Sanofi and Zealand Pharma. Leona Plum-Mörschel has received speaker honoraria and travel grants from Eli Lilly and Novo Nordisk. Eric Zijlstra has received speaker honoraria and travel grants from Novo Nordisk, Roche Diabetes Care and Senseonics.

Figures

Fig. 1
Fig. 1
Mean serum insulin 338 concentration–time profiles after oral administration and varying duration of post-dose fasting in healthy males. Error bars show standard error of the mean
Fig. 2
Fig. 2
Effect of post-dose fasting period on (a) AUCIns338,0–∞ and (b) Cmax,Ins338 after oral administration of insulin 338 in healthy males. Bars are estimated means and 95% CIs. Treatment comparisons show estimated treatment ratios [95% CI] and p value for the pairwise comparisons of 0, 30 and 60 min post-dose fasting with 360 min post-dose fasting. AUCIns338,0–∞ area under the concentration–time curve for insulin 338 from time zero to infinity, CI confidence interval, Cmax,Ins338 maximum concentration of insulin 338

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