Elsevier

Clinical Therapeutics

Volume 37, Issue 7, 1 July 2015, Pages 1503-1516
Clinical Therapeutics

Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers

https://doi.org/10.1016/j.clinthera.2015.05.002Get rights and content

Abstract

Purpose

The aim was to investigate the effects of coadministration of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione pioglitazone.

Methods

In study 1, 20 healthy volunteers received 50 mg of empagliflozin alone for 5 days, followed by 50 mg of empagliflozin coadministered with 45 mg of pioglitazone for 7 days and 45 mg of pioglitazone alone for 7 days in 1 of 2 treatment sequences. In study 2, 20 volunteers received 45 mg of pioglitazone alone for 7 days and 10, 25, and 50 mg of empagliflozin for 9 days coadministered with 45 mg of pioglitazone for the first 7 days in 1 of 4 treatment sequences.

Findings

Pioglitazone exposure (Cmax and AUC) increased when coadministered with empagliflozin versus monotherapy in study 1. The geometric mean ratio (GMR) for pioglitazone Cmax at steady state (Cmax,ss) and for AUC during the dosing interval at steady state (AUCτ,ss) when coadministered with empagliflozin versus administration alone was 187.89% (95% CI, 166.35%–212.23%) and 157.97% (95% CI, 148.02%–168.58%), respectively. Because an increase in pioglitazone exposure was not expected, based on in vitro data, a second study was conducted with the empagliflozin doses tested in Phase III trials. In study 2, pioglitazone exposure decreased marginally when coadministered with empagliflozin. The GMR for pioglitazone Cmax,ss when coadministered with empagliflozin versus administration alone was 87.74% (95% CI, 73.88%–104.21%) with empagliflozin 10 mg, 90.23% (95% CI, 66.84%–121.82%) with empagliflozin 25 mg, and 89.85% (95% CI, 71.03%–113.66%) with empagliflozin 50 mg. The GMR for pioglitazone AUCτ,ss when coadministered with empagliflozin versus administration alone was 90.01% (95% CI, 77.91%–103.99%) with empagliflozin 10 mg, 88.98% (95% CI, 72.69%–108.92%) with empagliflozin 25 mg, and 91.10% (95% CI, 77.40%–107.22%) with empagliflozin 50 mg. The effects of empagliflozin on pioglitazone exposure are not considered to be clinically relevant. Empagliflozin exposure was unaffected by coadministration with pioglitazone. Empagliflozin and pioglitazone were well tolerated when administered alone or in combination. In study 1, adverse events were reported in 1 of 19 participants on empagliflozin 50 mg alone, 4 of 20 on pioglitazone alone, and 5 of 18 on combination treatment. In study 2, adverse events were reported in 8 of 20 participants on pioglitazone alone, 10 of 18 when coadministered with empagliflozin 10 mg, 5 of 17 when coadministered with empagliflozin 25 mg, and 6 of 16 when coadministered with empagliflozin 50 mg.

Implications

These results indicate that pioglitazone and empagliflozin can be coadministered without dose adjustments. EudraCT identifiers: 2008-006087-11 (study 1) and 2009-018089-36 (study 2).

Introduction

The aim of therapy for type 2 diabetes mellitus (T2DM) is long-term glycemic control; however, attainment of this goal can be elusive.1 The continual decline in β-cell function over time means that most patients with T2DM will ultimately require >1 antidiabetic agent to maintain glycemic control.2

Empagliflozin is a potent and selective inhibitor of sodium glucose cotransporter 2 (SGLT2)3 used in the treatment of T2DM. By inhibiting SGLT2, empagliflozin reduces renal glucose reabsorption and thus increases urinary glucose excretion, leading to a reduction in plasma glucose. Because its mechanism of action is independent of insulin, empagliflozin is associated with a low risk of hypoglycemia and can be used in combination with all other classes of antidiabetic agents.4 Phase III trials have found that empagliflozin is effective at improving glycemic control and at reducing weight and blood pressure in patients with T2DM when used as monotherapy or add-on therapy to other antidiabetic agents.5, 6, 7, 8, 9

The pharmacokinetic properties of empagliflozin are similar in healthy volunteers and patients with T2DM.10, 11, 12 Empagliflozin is rapidly absorbed, with peak plasma concentrations occurring after a median of ~1.5 hours.11 Thereafter, plasma concentrations decline with a rapid distribution phase and a relatively slow terminal phase. The single-dose and steady-state pharmacokinetic properties of empagliflozin are similar, suggesting linear pharmacokinetic properties for time; systemic exposure to empagliflozin increases in a dose-proportional manner.11, 12 Empagliflozin undergoes limited metabolism, primarily glucuronidation, and is predominantly excreted unchanged in the urine and feces.13 Empagliflozin is a substrate of organic anion-transporting polypeptide 1B1/1B3, organic anion transporter 3,14 and P glycoprotein.15

Pioglitazone is an oral antidiabetic agent that selectively stimulates peroxisome proliferator-activated receptor γ, thus increasing the transcription of insulin-sensitive genes involved in the control of glucose and lipid metabolism. As a result, pioglitazone reduces insulin resistance in the liver and peripheral tissues.16, 17 Several studies have found that greater improvements in glycemic control can be achieved when pioglitazone is administered with other agents than with either agent alone.18, 19, 20, 21, 22, 23, 24, 25

Pioglitazone is rapidly absorbed, reaching maximum plasma concentrations in ~1.5 hours. Plasma levels then decline biphasically with a terminal half-life of ~9 hours.26, 27 Pioglitazone is metabolized in the liver by cytochrome (CYP) 450 enzymes, mainly CYP2C8, which are known mediators of drug–drug interactions.28 Six metabolites were described, 3 of which, M-II, M-III and M-IV, are pharmacologically active, although M-II concentrations are relatively low and do not contribute substantially to total pharmacologic activity.27 Formation of the M-IV metabolite is catalyzed predominantly by CYP2C8, whereas M-III is a derivative of M-IV.28

No interaction between empagliflozin and pioglitazone was expected, because the metabolic/disposition pathways of empagliflozin and pioglitazone do not overlap,13, 14, 15, 28 and given that empagliflozin does not inhibit, inactivate, or induce the major CYP450 isozymes that can cause drug–drug interactions with pioglitazone (data on file). However, given the possibility that empagliflozin and pioglitazone may be administered together in clinical practice, we investigated the effect of empagliflozin on the pharmacokinetic properties of pioglitazone and its metabolites after coadministration in healthy volunteers.

Section snippets

Methods

A randomized, open-label, crossover study was conducted in healthy volunteers to investigate the effects of coadministration of multiple doses of 50 mg of empagliflozin (the highest dose of empagliflozin investigated in dose-finding studies) and 45 mg of pioglitazone (the maximum recommended dose of pioglitazone) (study 1). Because of unexpected findings in this study, a second randomized, open-label, crossover study was conducted (study 2). In study 2, empagliflozin was administered at the

Participants

All study participants were white men. Baseline characteristics were similar across all treatment groups (Table I). In study 1, 16 of 20 randomly assigned participants completed the trial. One participant discontinued because of an adverse event (not considered related to study drug), 1 participant was withdrawn from the trial because of a lack of compliance, and 2 participants withdrew informed consent. In study 2, 15 of 20 randomly assigned participants completed the trial; discontinuations

Discussion

A randomized, open-label, crossover study was conducted to investigate the effects of coadministration of multiple doses of 50 mg of empagliflozin and 45 mg of pioglitazone in healthy volunteers. In this study, an increase in pioglitazone exposure at steady state (AUCτ,ss and Cmax,ss) was observed when it was coadministered with empagliflozin. Similar increases were seen for the pioglitazone metabolites M-III and M-IV. An interaction between empagliflozin and pioglitazone was not anticipated,

Conclusion

These results suggest that no clinically relevant drug–drug interactions exist between empagliflozin and pioglitazone and that no dose adjustment is warranted when these drugs are given concomitantly.

Conflicts of Interest

All the authors except S. Macha are employees of Boehringer Ingelheim. S. Macha was an employee of Boehringer Ingelheim at the time that these studies were conducted.

Acknowledgements

These studies were funded by Boehringer Ingelheim and Eli Lilly and Company. Boehringer Ingelheim was involved in the design of the study, data collection and analysis, and the writing of the manuscript. Eli Lilly and Company’s involvement was limited to co-funding of the study.

We thank Andreas Port for contribution to the planning and conduct of the studies and for support in preparing the clinical trial reports; Lois S. Rowland from Boehringer Ingelheim Pharmaceuticals, Inc. and BASi

References (31)

  • H.U. Haering et al.

    Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial

    Diabetes Care

    (2013)
  • H.U. Haering et al.

    Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial

    Diabetes Care

    (2014)
  • L. Seman et al.

    Empagliflozin (BI 10773), a potent and selective SGLT-2 inhibitor, induces dose-dependent glucosuria in healthy subjects

    Clinical Pharmacol Drug Dev

    (2013)
  • T. Heise et al.

    Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks׳ treatment with empagliflozin once daily in patients with type 2 diabetes

    Diabetes Obes Metab

    (2013)
  • T. Heise et al.

    Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus

    Diabetes Ther

    (2013)
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