Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers
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
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