Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial

Abstract

Aims: To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development.

Methods: We conducted a single-dose, open-label, randomized, parallel-group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10-17 years.

Results: Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd) age was 14.1±2.0 years and body weight was 96.7±23.5 kg. Compared with similar studies in adults with Type 2 diabetes, the maximum observed plasma concentrations were slightly lower with the 10-mg and 25-mg doses, and the area under the plasma concentration-time curve was slightly lower with the 10-mg but slightly higher with the 25-mg dose. The adjusted mean increases in urinary glucose excretion were 53 g/24 h (95% CI 32,74), 73 g/24 h (95% CI 52,94) and 87 g/24 h (95% CI 68,107), and the adjusted mean decreases in fasting plasma glucose were 0.9 mmol/l (95% CI -1.6,-0.1), 0.9 mmol/l (95% CI -1.7,-0.2) and 1.1 mmol/l (95% CI -1.8,-0.5) for the 5- 10- and 25-mg doses, respectively. There were no serious adverse events and one investigator-reported drug-related event (dehydration).

Conclusions: After a single oral dose of empagliflozin, adults and young people with Type 2 diabetes had similar exposure-response relationships after adjusting for significant covariates. These data support testing 10-mg and/or 25-mg doses of empagliflozin in an upcoming paediatric phase III Type 2 diabetes trial. (ClinicalTrials.gov registration no.: NCT02121483).

© 2018 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Figures

Figure 1

Arithmetic mean concentration–time profiles of empagliflozin in plasma, (a) linear scale and (b) log scale, and (c) simulated exposure–response profile. (a and b) The mean empagliflozin plasma concentration for the 5‐mg dose group at 48 h post dose was not calculated as only three individual values were available at this time point. As predefined, descriptive statistics of concentrations at specific time points were calculated only if at least two‐thirds of the participants had concentrations within the validated concentration range. (c) Pink line: median of simulations, pink shaded area: 95% CI of simulated median. Small circles: change from baseline in 24‐h urinary glucose excretion for an adult participant at the median 24‐h area under the concentration–time curve in the respective dose group of the simulations [typical adult person: 58‐year‐old male with Type 2 diabetes; baseline mean daily glucose: 6.9 mmol/l (adjusted to typical value for paediatric patient)]. Large circles: geometric mean (gMean) change from baseline in 24‐h urinary glucose excretion for paediatric participant at the gMean 24‐h area under the curve in the respective dose group. Error bars: 95% CI of the gMeans in each dose group in paediatric participants, calculated as gMean ± 1.96×se.

Figure 2

Mean changes from baseline in urinary glucose excretion (including 95% CIs) on day 1 (adjusted for baseline urinary glucose excretion and fasting plasma glucose).

Figure 3

Mean changes from baseline in fasting plasma glucose (including 95% confidence intervals) after 24 h (adjusted for baseline fasting plasma glucose). Analysis includes only patients with both a baseline and on‐treatment fasting plasma glucose value.