Clinical Therapeutics/Volume 37, Number 7, 2015

Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers Sreeraj Macha, MD1; Michaela Mattheus2; Sabine Pinnetti, MD3; Uli C. Broedl, MD2; and Hans J. Woerle, MD2 1

Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut; 2Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; and 3Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany

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

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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: 2008-00608711 (study 1) and 2009-018089-36 (study 2). (Clin Ther. 2015;37:1503–1516) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: diabetes, drug–drug interaction, SGLT2 inhibitor, thiazolidinedione.

INTRODUCTION The aim of therapy for type 2 diabetes mellitus (T2DM) is long-term glycemic control; however, Accepted for publication May 6, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.002 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics 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 41 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.5–9 The pharmacokinetic properties of empagliflozin are similar in healthy volunteers and patients with T2DM.10–12 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 proliferatoractivated 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.18–25 Pioglitazone is rapidly absorbed, reaching maximum plasma concentrations in  1.5 hours. Plasma levels then decline biphasically with a terminal halflife of  9 hours.26,27 Pioglitazone is metabolized in the liver by cytochrome (CYP) 450 enzymes, mainly

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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,13–15,28 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.

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 doses under investigation in Phase III trials (10 and 25 mg) in addition to the 50 mg dose administered in study 1.

Participants Male volunteers aged 18 to 50 years with a body mass index of 18.5 to 29.9 kg/m2 and in good general health (according to medical history, physical examination, vital signs, 12-lead electrocardiogram [ECG], laboratory tests) were recruited for study 1. Volunteers were excluded if they had evidence or history of a clinically relevant concomitant disease, smoked or abused alcohol or drugs, or had participated in another trial with an investigational drug in the previous 2 months. The inclusion and exclusion criteria for participants in study 2 were the same as those for study 1, except that the upper age limit was 55 years.

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S. Macha et al. All participants gave signed informed consent before admission to the studies.

Study Designs In both studies, participants were randomly assigned with the use of a computer-generated code. In study 1, 20 participants were randomized to receive 3 treatments: 50 mg of empagliflozin administered once daily for 5 days (A), followed by once daily treatment with 50 mg of empagliflozin and 45 mg of pioglitazone in combination for 7 days (B), and 45 mg of pioglitazone once daily for 7 days (C). The 3 treatments were delivered in 1 of 2 sequences: AB then C or C then AB, with a washout period of Z7 days between treatments AB and C or between treatments C and AB. Empagliflozin alone and pioglitazone alone were administered after an overnight fast of  10 hours on pharmacokinetic assessment days (day 5 [A] and day 7 [C]). In study 2, 20 volunteers received 4 treatments (45 mg of pioglitazone alone [A] and in combination with 10 mg [B], 25 mg [C], or 50 mg [D] of empagliflozin) in 1 of 4 treatment sequences (ADBC, BACD, CBDA, or DCAB). A total of 9 doses of empagliflozin was administered on days 1 through 9 in each of treatments B, C, and D, and a total of 7 doses of pioglitazone were administered on days 1 through 7 in each of treatments A, B, C, and D, with a washout period of at least 6 days between empagliflozin treatments and 8 days between pioglitazone treatments. Study drugs were administered once daily at the same time each day. On pharmacokinetic profile days (days 1 and 7), the drug was administered after an overnight fast of 10 hours. Standardized meals were served 4 hours after drug administration. Both studies were conducted at the Human Pharmacology Centre, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach am Riss, Germany. They were performed in accordance with the Clinical Trial Protocol, approved by the Bundesinstitut für Arzneimittel und Medizinprodukte (Bonn, Germany), the Ethical Principles for Medical Research Involving Human Subjects of the Declaration of Helsinki (October 1996), the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonized Tripartite Guideline for Good Clinical Practice, standard operating procedures of Boehringer Ingelheim, and applicable regulatory requirements.

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Pharmacokinetic Methods In study 1, a total of 310 mL of blood was taken from every participant. For pharmacokinetic analyses of empagliflozin (treatments A and B) and pioglitazone (treatments B and C), blood was collected before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 24 hours after dosing on day 5 (treatment A) or day 7 (treatments B and C), plus additional collections 36, 48, and 72 hours after dosing for treatments B and C. Additional samples before dosing were collected on days 1, 3, and 4 of treatment A, and on days 1 through 6 of treatments B and C. Urine was collected on days 5 (treatment A) or 7 (treatments B and C); all urine was voided within the 1-hour interval before dosing and in 0- to 2-, 2- to 4-, 4- to 8-, 8- to 12-, and 12- to 24-hour intervals after dosing was collected. In study 2, a total of 442 mL of blood was taken from every participant. For quantitation of pioglitazone and its metabolites, blood was collected before dosing; at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dosing on days 1 and 7; and at 36, 48, and 72 hours after dosing on day 7. Additional samples before dosing were taken on days 3 through 6 for assessment of steady state. Empagliflozin trough levels were determined by measuring plasma concentrations of empagliflozin before dosing at selected time points during coadministration of empagliflozin and pioglitazone. All urine voided within the 1-hour interval before dosing and in 0- to 4-, 4- to 8-, 8- to 12-, and 12- to 24-hour intervals after dosing was collected on days 1 and 7. In both studies, plasma concentrations of empagliflozin, pioglitazone, and M-III and M-IV metabolites of pioglitazone and urine concentrations of pioglitazone and its metabolites were determined with a validated highpressure liquid chromatography tandem mass spectrometry method. The calibration curve was linear and validated for pioglitazone in plasma and urine for the range of 2.5 to 2500 ng/mL in study 1 (and M-III and MIV in both studies) and 1 to 1000 ng/mL in study 2. The lower limit of quantitation for empagliflozin in plasma was 1.11 nmol/L, with linearity up to 1110 nmol/L.

Pharmacokinetic End Points In study 1, the primary end points used to evaluate the pharmacokinetic properties of empagliflozin and pioglitazone after coadministration versus dosing alone were AUC over the dosing interval (τ) at steady

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Clinical Therapeutics state (AUCτ,ss) and Cmax at steady state (Cmax,ss) of empagliflozin and pioglitazone. Secondary pharmacokinetic end points for pioglitazone included time to Cmax,ss (tmax,ss) and terminal elimination half-life at steady state (t½,ss). Analysis of these parameters for pioglitazone metabolites M-III and M-IV was performed post hoc. In study 2, the primary pharmacokinetic end points used to evaluate the pharmacokinetic properties of pioglitazone after coadministration with empagliflozin versus dosing alone were AUCτ,ss and Cmax,ss of pioglitazone in plasma. Secondary pharmacokinetic end points for pioglitazone, M-III, and M-IV after single doses and at steady state were AUC, Cmax, tmax, and t½. Trough concentrations of empagliflozin in plasma were measured for treatments B, C, and D. Pharmacokinetic parameters were calculated with WinNonlin software, version 5.2 (Pharsight Corporation, Mountain View, California). Cmax and tmax values were determined directly from the plasma concentration time profiles of each participant. Τhe terminal elimination rate constant of the drug in plasma (λz) was estimated from a regression of ln(C) versus time over the terminal log-linear drug disposition portion of the concentration–time profiles. t½ was calculated as the quotient of ln(2) and λz. AUC to the last time point was calculated with the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The AUC0–1 value was estimated as the sum of AUC to the last measured concentration, with the extrapolated area given by the quotient of the last measured concentration and λz.

Pharmacodynamic End Points Cumulative glucose excretion over the time interval of 0 to 24 hours (UGE0–24) was assessed in study 1. Pharmacodynamic end points were not assessed in study 2.

Safety End Points In both studies, the safety profile evaluations were based on physical examinations, monitoring of vital signs (blood pressure, pulse rate), 12-lead ECGs, clinical laboratory tests (hematology, clinical chemistry, urinalysis), and recording of adverse events. Adverse events were coded with the Medical Dictionary for Drug Regulatory Activities (version 12.0 for study 1 and version 12.1 for study 2). Vital signs

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and 12-lead ECGS were assessed at screening and at the end-of-study examination. Clinical laboratory tests were conducted at screening, on the day of first dose, and the last day of each treatment period in study 1, and at screening and at the end of the each treatment period in study 2.

Statistical Analysis The statistical analyses for each study were performed separately. All participants who provided Z1 observation for Z1 primary pharmacokinetic end points without any protocol violations relevant to the evaluation of pharmacokinetic properties were included in the analysis of primary end points (pharmacokinetic set). The statistical models used for the analyses of AUCτ,ss and Cmax,ss of pioglitazone (and metabolites) and empagliflozin were ANOVA models applied after log-transformation of the data. To account for the design of the studies, that is, the order of treatments participants were exposed to and the within-subject variability, the model used for pioglitazone analyses included effects of treatment, period, sequence, and subject within sequence, and the model for empagliflozin analyses included effects of subject and treatment. The effects of subject and subject within sequence were considered random. The difference in least-square means and 90% CIs obtained from the ANOVAs on log-transformed data were finally back-transformed to the original scale to obtain the geometric mean ratio (GMR) and corresponding 2-sided 90% CIs. Safety profile analyses were descriptive and were performed on the treated set, defined as participants who took Z1 dose of study treatment.

RESULTS 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 were because of adverse events (n ¼ 2), noncompliance with the protocol (n ¼ 2), and withdrawal of consent (n ¼ 1).

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July 2015 Table I. Baseline demographic characteristics (treated set). Study 2 Sequences†

Study 1 Sequences* Characteristics Participants, n Age, median (range), years Height, median (range), cm Weight, median (range), kg BMI, median (range), kg/m2

ABC

CAB

ADBC

BACD

CBDA

DCAB

10 35.0 (2443)

10 29.0 (2047)

5 32.0 (2345)

5 38.0 (2343)

5 31.0 (2050)

5 35.0 (2839)

182.5 (172194)

183.0 (173196)

178.0 (172183)

179.0 (167184)

179.0 (170189)

179.0 (170185)

86.5 (70105)

81.5 (7194)

84.0 (6387)

73.0 (6377)

86.0 (7692)

75.0 (7284)

25.40 (23.028.4)

23.95 (19.028.1)

25.40 (21.027.5)

22.70 (22.523.6)

26.90 (23.728.1)

24.50 (21.724.9)

BMI ¼ body mass index. * Study 1 treatments were as follows: A, 50 mg of empagliflozin alone; B, 45 mg of pioglitazone with 50 mg of empagliflozin; and C, 45 mg of pioglitazone alone, all once daily, with a washout period of Z7 days between treatments AB and C or between treatments C and AB. † Study 2 treatments were as follows: A, 45 mg of pioglitazone alone; B, 45 mg of pioglitazone with 10 mg of empagliflozin; C, 45 mg of pioglitazone with 25 mg of empagliflozin; and D, 45 mg of pioglitazone with 50 mg of empagliflozin, all once daily, with a washout period of 6 days between empagliflozin treatments and 8 days between pioglitazone treatments.

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Pharmacokinetics of Pioglitazone In study 1, pioglitazone was rapidly absorbed, reaching peak levels 2 hours after oral administration. Thereafter, plasma levels declined in a biphasic fashion with a rapid distribution phase and a slower elimination phase. After multiple daily doses, pioglitazone exposure reached steady state by day 7. The t½,ss of pioglitazone decreased when coadministered with empagliflozin (15.6 vs 7.9 hours; Table II). Exposure of pioglitazone was higher when coadministered with 50 mg of empagliflozin than when given alone, with mean values for AUCτ,ss of 14,000 versus 9330 ng·h/mL and mean values for Cmax,ss of 1960 versus 1140 ng/mL (Figure 1A and B; Table II). Exposure of the metabolites M-III and M-IV also increased when pioglitazone was coadministered with empagliflozin (Table II), contributing to an increase in overall exposure of active moieties by  24% after coadministration with empagliflozin, compared with administration of pioglitazone alone (47,900 vs 38,630 ng·h/mL). Because no interaction between empagliflozin and pioglitazone was expected, based on in vitro data, a second study (study 2) was conducted with the empagliflozin doses tested in Phase III trials. In study 2, pioglitazone exposure at steady state (Cmax,ss and AUCτ,ss) after administration of pioglitazone alone was similar to that observed in study 1 (Table III; Figure 2A). The t½,ss (day 7) was similar to that observed after the first dose (11.3 hours and 10.8 hours, respectively; Table III), indicating linear pharmacokinetic properties for time. Consistent with the t½,ss, 20% accumulation was observed at steady state when pioglitazone was administered alone, whereas accumulation of pioglitazone was only 3% to 5% when administered with empagliflozin. As a result, although pioglitazone exposure after a single dose was similar when given with or without empagliflozin, exposure of pioglitazone at steady state was slightly lower when pioglitazone was coadministered with empagliflozin than when given alone (Table III). The adjusted GMRs for pioglitazone AUCτ,ss and Cmax,ss ranged from  88% to 91%. The lower limits of 90% CIs ranged from 67% to 78%, thus falling below the standard bioequivalence boundaries of 80% to 125% (Table IV). In study 2, exposure of the pioglitazone metabolites M-III and M-IV was similar when pioglitazone was given with or without empagliflozin (Table III).

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Adjusted GMRs for AUCτ,ss ranged from  95% to 101%, and the 90% CIs were within the standard bioequivalence boundaries (lower limits ranging from 85% to 92% and upper limits from 101% to 113%; Table IV). However, adjusted GMRs for Cmax,ss ranged from 89% to 112%, and their 90% CIs were slightly outside the standard bioequivalence boundaries (lower limits ranging from 76%–91% and upper limits from 103%–139%; Table IV). Although it was not possible to determine with accuracy the t½ of M-III or M-IV, because of their relatively long t½, the t½,ss of both metabolites were similar whether pioglitazone was administered alone or with empagliflozin (23.2 hours with pioglitazone alone vs 23.0–26.9 hours with empagliflozin for both M-III and M-IV; Table III). As expected, roughly 3-fold accumulation was observed for both M-III and M-IV with repeated administration of pioglitazone, with or without empagliflozin (Figure 2B and C). Urine concentrations of pioglitazone and M-III were below the limit of quantitation in most participants both on day 1 and at steady state. Low levels of M-IV were detected in urine ( 0.15%–0.18% of the administered dose at steady state) when pioglitazone was given alone. When pioglitazone was coadministered with empagliflozin, the total amount of M-IV excreted in urine decreased slightly by 8% to 15% (data not shown).

Pharmacokinetics of Empagliflozin In study 1, peak plasma levels of empagliflozin were reached at 1.7 hours when administered alone and at 2 hours when coadministered with pioglitazone (Table II). No differences were found in empagliflozin exposure when it was administered alone compared with when administered with pioglitazone (mean AUCτ,ss: 8990 vs 8980 nmol·h/mL; mean Cmax,ss: 1370 vs 1280 nmol/L, respectively; Table II). Adjusted GMRs were 100.32 (90% CI, 96.08–104.75) for AUCτ,ss and 93.44 (90% CI, 85.08–102.62) for Cmax,ss (Table IV). In study 2, increases in plasma trough concentrations were approximately dose proportional from 10 to 50 mg of empagliflozin when coadministered with pioglitazone 45 mg (data not shown). Empagliflozin trough levels with 50 mg of empagliflozin coadministered with 45 mg of pioglitazone were similar to study 1 (data not shown).

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July 2015 Table II. Summary of mean (%CV) pharmacokinetic parameters of empagliflozin and pioglitazone after administration of 50 mg of empagliflozin and 45 of mg pioglitazone alone or in combination (study 1). Empagliflozin

Parameter

Pioglitazone

Empagliflozin þ Empagliflozin þ Empagliflozin pioglitazone Pioglitazone pioglitazone (n ¼ 18) (n ¼ 17) (n ¼ 20) (n ¼ 17)

8990 (12.4) 8980 AUCτ,ss* Cmax,ss† 1370 (18.8) 1280 1.7 (1.03.0) 2.0 tmax,ss, median (range), h t½,ss, h 8.6 (15.5) 11.7

M-III Pioglitazone (n ¼ 20)

Empagliflozin þ pioglitazone (n ¼ 17)

M-IV Pioglitazone (n ¼ 20)

Empagliflozin þ pioglitazone (n ¼ 17)

(10.5) 9330 (31.6) 14000 (22.5) 8700 (31.7) 10200 (15.7) 20600 (30.9) 23700 (17.6) (15.3) 1140 (39.7) 1960 (16.3) 463 (32.5) 532 (15.4) 1030 (31.3) 1240 (16.7) (1.53.0) 1.8 (0.74.0) 2.0 (1.03.0) 5.0 (2.510.0) 8.0 (3.012.1) 4.0 (1.012.0) 4.0 (2.510.0)

(36.9)

15.6 (57.1)

7.9 (39.0)

22.2 (15.4)

20.5 (14.3)

22.1 (19.1)

21.6 (25.1)

AUCτ,ss ¼ AUC during a dosing interval (τ) at steady state; Cmax,ss ¼ Cmax during a dosing interval at steady state; tmax,ss ¼ time to Cmax,ss; t½,ss ¼ terminal elimination half-life at steady state. * AUC: nmol·h/mL for empagliflozin; ng·h/mL for pioglitazone, M-III, and M-IV. † Cmax,ss: nmol/L for empagliflozin; ng/mL for pioglitazone, M-III, and M-IV.

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Pioglitazone plasma concentration (ng/mL)

A 2500 2250 45 mg Pioglitazone 45 mg Pioglitazone + 50 mg Empagliflozin

2000 1750 1500 1250 1000 750 500 250 0 0

Empagliflozin plasma concentration (nmol/L)

B

6

12

18

24 Time (h)

30

36

42

48

1600 1400 1200 50 mg Empagliflozin 1000

50 mg Empagliflozin + 45 mg Pioglitazone

800 600 400 200 0 0

6

12 Time (h)

18

24

Figure 1. Mean (SD) plasma concentration–time profiles from study 1 for pioglitazone (A) and empagliflozin (B). Treatment A: 50 mg of empagliflozin alone; treatment B: 45 mg of pioglitazone with 50 mg of empagliflozin; treatment C: 45 mg of pioglitazone alone, all once daily, with a washout period of Z7 days between treatments AB and C or between treatments C and AB.

Pharmacodynamics of Empagliflozin UGE was assessed in study 1. Consistent with the mode of action of empagliflozin, increased UGE was observed after administration of empagliflozin alone and in combination with pioglitazone (data not shown).

Safety and Tolerability In study 1, 9 of 20 participants reported Z1 adverse event: 1 of 19 (5.3%) with empagliflozin alone, 4 of 20 (20.0%) with pioglitazone alone, and

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5 of 18 (27.8%) with combination treatment (Table V). All the adverse events were mild or moderate in intensity. The most frequently reported adverse event was headache (2 participants). In study 2, 17 of the 20 participants (85%) reported Z1 adverse event. The percentage of participants who reported Z1 adverse event was similar when pioglitazone was administered alone (40.0%) and with 10, 25, and 50 mg of empagliflozin (29.4%– 55.6%; Table V). No participant experienced a severe or serious adverse event. No clinically relevant

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Table III. Mean (%CV) pharmacokinetic parameters of pioglitazone and M-III and M-IV metabolites after oral administration of 45 mg of pioglitazone once daily alone and with empagliflozin once daily (study 2).

Parameter

Pioglitazone 45 mg alone

Pioglitazone 45 mg þ Empagliflozin 10 mg

Pioglitazone 45 mg þ Empagliflozin 25 mg

Pioglitazone 45 mg þ Empagliflozin 50 mg

Pioglitazone Single dose 8670 (28.2) 8410 (33.1) — 8960 (33.1) AUC0–24, ng·h/mL Cmax, ng/mL 908 (35.5) 924 (37.3) — 1020 (38.0) 2.0 (0.54.0) 1.75 (0.54.0) — 2.0 (1.04.0) tmax, median (range), h 10.8 (52.0) 9.6 (30.7) — 8.8 (40.5) t½, h Steady state 10,500 (38.2) 8820 (22.0) 9200 (39.7) 9200 (31.4) AUCτ,ss, ng·h/mL 1260 (60.9) 988 (29.3) 1110 (60.1) 1060 (37.5) Cmax,ss, ng/mL tmax,ss, median 2.0 (0.58.0) 2.0 (1.04.0) 2.0 (0.58.0) 1.5 (0.56.0) (range), h t½,ss, h 11.3 (48.9) 12.3 (59.8) 12.2 (68.1) 13.2 (41.7) M-III Single dose 3350 (45.7) 3310 (31.2) — 3480 (42.2) AUC0–24, ng·h/mL 188 (42.9) 183 (31.2) — 192 (46.7) Cmax, ng/mL tmax, median (range), h 12.0 (10.023.9) 11.0 (6.023.9) — 12.0 (10.023.9) Steady state 10,200 (40.5) 9740 (39.5) 9910 (39.4) 9510 (35.6) AUCτ,ss, ng·h/mL Cmax,ss, ng/mL 626 (77.5) 514 (36.4) 601 (82.1) 497 (36.2) 6.0 (1.510.0) 6.0 (010.0) 6.0 (112.0) 5.0 (2.012.0) tmax,ss, median (range), h 23.2 (17.8) 24.8 (26.8) 23.0 (21.7) 25.6 (36.6) t½,ss, h M-IV Single dose 8130 (29.8) 8040 (25.2) — 8370 (30.4) AUC0–24, ng·h/mL Cmax, ng/mL 438 (26.1) 432 (26.9) — 449 (28.1) 17.9 (8.023.9) 17.9 (8.023.9) — 12.0 (8.023.9) tmax, median (range), h Steady state 24,600 (25.4) 23,100 (24.3) 25,000 (34.3) 22,800 (25.4) AUCτ,ss, ng·h/mL 1430 (74.8) 1190 (25.0) 1540 (68.4) 1140 (27.7) Cmax,ss, ng/mL 4.0 (2.012.0) 4.0 (0.512.0) 4.0 (1.012.0) 4.0 (1.512.0) tmax,ss, median (range), h 23.2 (21.5) 24.5 (23.7) 25.2 (24.2) 26.9 (31.9) t½,ss, h AUCτ,ss ¼ AUC during a dosing interval (τ) at steady state; Cmax,ss ¼ Cmax during a dosing interval at steady state; tmax,ss ¼ time to Cmax,ss; t½,ss ¼ terminal elimination half-life at steady state. Samples were not collected for the pioglitazone þ 25-mg empagliflozin group after a single dose because of restrictions on blood volumes.

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Clinical Therapeutics

B

1500

1250

45 mg Pioglitazone 45 mg Pioglitazone + 10 mg Empagliflozin 45 mg Pioglitazone + 25 mg Empagliflozin 45 mg Pioglitazone + 50 mg Empagliflozin

1250 1000

M-III plasma concentration (ng/mL)

Pioglitazone plasma concentration (ng/mL)

A

750 500 250

45 mg Pioglitazone 45 mg Pioglitazone + 10 mg Empagliflozin 45 mg Pioglitazone + 25 mg Empagliflozin 45 mg Pioglitazone + 50 mg Empagliflozin

1000 750 500 250 0

0 0

12

24 144

156

168

180

192

204

216

0

12

24 144

156

Time (h)

M-IV plasma concentration (ng/mL)

C

168

180

192

204

216

Time (h)

2500 2250 2000 1750 1500 1250 1000 750 500 250 0

45 mg Pioglitazone 45 mg Pioglitazone + 10 mg Empagliflozin 45 mg Pioglitazone + 25 mg Empagliflozin 45 mg Pioglitazone + 50 mg Empagliflozin

0

12

24 144

156

168

180

192

204

216

Time (h)

Figure 2. Mean (SD) plasma concentration–time profiles from study 2 for pioglitazone (A), M-III metabolite (B), and M-IV metabolite (C); 45 mg of pioglitazone was administered alone and with 10, 25, or 50 mg of empagliflozin. Empagliflozin was administered once daily on days 1 to 9, and pioglitazone was administered once daily on days 1 to 7 of relevant treatment periods, with a washout period of 6 days between empagliflozin treatments and 8 days between pioglitazone treatments. Samples were not collected for the pioglitazone þ 25 mg of empagliflozin group (treatment C) after a single dose, because of restrictions on blood volumes.

changes were found in clinical laboratory parameters or vital signs.

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, because the metabolic/disposition pathways of empagliflozin and pioglitazone do not overlap,13–15,28 and empagliflozin does not inhibit, inactivate, or induce the major CYP450 isozymes that can cause drug–drug interactions with pioglitazone (data on file). Thus, a second randomized, open-label, crossover study was

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conducted, which investigated the effects of coadministration of multiple doses of empagliflozin (10, 25, and 50 mg) and 45 mg of pioglitazone in healthy volunteers. In this study, coadministration of pioglitazone with empagliflozin had no effect on exposure to M-III and M-IV, although the AUCτ,ss and Cmax,ss of pioglitazone were marginally lower at steady state than when it was given alone. No reason was evident for the differences in results between the studies. Study 1 had a crossover design with 2 treatments comprising pioglitazone and empagliflozin/pioglitazone þ empagliflozin separated by a washout phase, whereas study 2 had a complete crossover (balanced Latin square) design with a washout between treatments. This difference in study design would not be expected to result in different results. A difference in food intake was also considered; in study 1, a light snack was given to participants in the combination arm before drug administration, whereas in study 2, participants

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S. Macha et al.

Table IV. Adjusted GMRs and 90% CIs for AUCτ,ss and Cmax,ss of pioglitazone, its metabolites M-III and M-IV, and empagliflozin after oral administration of pioglitazone and empagliflozin in combination versus administration alone. Treatment

Parameter

GMR (%)

Study 1 (relative to empagliflozin or pioglitazone treatment alone) Empagliflozin Pioglitazone 45 mg þ empagliflozin 50 mg AUCτ,ss Cmax,ss Pioglitazone Pioglitazone 45 mg þ empagliflozin 50 mg AUCτ,ss Cmax,ss Study 2 (relative to 45 mg of pioglitazone alone) Pioglitazone Pioglitazone 45 mg þ empagliflozin 10 mg AUCτ,ss Cmax,ss Pioglitazone 45 mg þ empagliflozin 25 mg AUCτ,ss Cmax,ss Pioglitazone 45 mg þ empagliflozin 50 mg AUCτ,ss Cmax,ss M-II Pioglitazone 45 mg þ empagliflozin 10 mg AUCτ,ss Cmax,ss Pioglitazone 45 mg þ empagliflozin 25 mg AUCτ,ss Cmax,ss Pioglitazone 45 mg þ empagliflozin 50 mg AUCτ,ss Cmax,ss M-IV Pioglitazone 45 mg þ empagliflozin 10 mg AUCτ,ss Cmax,ss Pioglitazone 45 mg þ empagliflozin 25 mg AUCτ,ss Cmax,ss Pioglitazone 45 mg þ empagliflozin 50 mg AUCτ,ss Cmax,ss

90% CIs for GMR

gCV (%)

100.32 93.44

(96.08–104.75) (85.08–102.62)

7.3 15.9

157.97 187.89

(148.02–168.58) (166.35–212.23)

10.8 20.7

90.01 87.74 88.98 90.23 91.10 89.85

77.91–103.99 73.88–104.21 72.69–108.92 66.84–121.82 77.40–107.22 71.03–113.66

24.6 29.5 33.9 52.6 26.4 39.1

99.39 95.70 99.46 103.63 98.88 91.90

87.37–113.07 77.28–118.50 89.11–111.02 80.83–132.86 90.73–107.77 77.12–109.51

21.9 37.2 17.8 42.0 13.6 28.3

94.98 92.57 100.57 112.46 96.13 88.96

85.31–105.74 77.28–110.89 91.57–110.46 90.82–139.26 91.93–100.52 76.49–103.48

18.2 31.1 15.1 35.6 7.0 24.3

AUCτ,ss ¼ AUC during a dosing interval (τ) at steady state; Cmax,ss ¼ Cmax during a dosing interval at steady state; gCV ¼ intra-individual geometric CV; GMR ¼ geometric mean ratio.

fasted overnight. Previous studies suggest that this is unlikely to result in different outcomes; no clinically relevant changes in empagliflozin exposure were observed when empagliflozin was administered with a high-fat, high-calorie meal,10,29 and food has no clinically relevant effect on pioglitazone exposure.30 The changes in pioglitazone exposure observed in both studies were not considered clinically relevant.

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Neither the increase in overall exposure to active moieties of pioglitazone of 22% when it was administered with 50 mg of empagliflozin in study 1 nor the slight decreases in exposure to pioglitazone when it was administered with empagliflozin 10, 25, and 50 mg in study 2 would warrant dose adjustment when pioglitazone and empagliflozin are coadministered. Studies of other agents given in combination

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Clinical Therapeutics

1514 Table V. Adverse events (treated set). Study 1

Participants, n Any adverse event, n (%) Investigator-defined drug-related adverse event, n (%) Headache, n (%) Fatigue, n (%) Nasopharyngitis, n (%) Conjunctivitis, n (%) Diarrhea, n (%) Nausea, n (%) Dizziness, n (%)

Study 2

Empagliflozin 50 mg

Pioglitazone 45 mg þ Empagliflozin 50 mg

19 1 (5.3) 1 (5.3)

18 5 (27.8) 0

20 4 (20.0) 3 (15.0)

20 8 (40.0) 3 (15.0)

18 10 (55.6) 8 (44.4)

17 5 (29.4) 3 (17.6)

16 6 (37.5) 6 (37.5)

0 0 0 0 0 0 0

0 0 1 (5.6) 1 (5.6) 0 0 0

2 (10.0) 0 0 0 0 0 0

5 (25.0) 0 1 (5.0) 0 0 1 (5.0) 1 (5.0)

3 (16.7) 3 (16.7) 1 (5.6) 1 (5.6) 0 0 1 (5.6)

1 (5.9) 0 1 (5.9) 1 (5.9) 1 (5.9) 0 0

3 (18.8) 2 (12.5) 1 (6.3) 0 1 (6.3) 1 (6.3) 0

Pioglitazone Pioglitazone 45 mg 45 mg

Adverse events shown are those reported in Z10% of participants in Z1 of the studies.

Pioglitazone 45 mg þ Empagliflozin 10 mg

Pioglitazone 45 mg þ Empagliflozin 25 mg

Pioglitazone 45 mg þ Empagliflozin 50 mg

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S. Macha et al. with pioglitazone have also noted changes in the pharmacokinetic properties of pioglitazone, which were not considered to warrant dose adjustment. For example, exposure of a single 15-mg dose of pioglitazone increased 43-fold when coadministered with the fibrate gemfibrozil,31 and no dose adjustment of pioglitazone is warranted when it is coadministered with gemfibrozil.30 Coadministration of empagliflozin and pioglitazone was well tolerated in both studies. Empagliflozin had no effect on the frequency or intensity of adverse events in participants treated with pioglitazone. Most adverse events were mild, and no participants experienced hypoglycemia.

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.

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 cofunding 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 (Bioanalytical Systems Inc.), West Lafayette, Indiana, for bioanalytical work; and Mitchell Taub from Boehringer Ingelheim Pharmaceuticals, Inc. for contribution to the in vitro data. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Isobel Lever and Wendy Morris of Fleishman-Hillard Group Ltd, during the preparation of this manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.

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.

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Address correspondence to: Uli C. Broedl, Boehringer Ingelheim Pharma GmbH & Co KG, Binger Strasse 173, Ingelheim 55216, Germany. E-mail: [email protected]

Volume 37 Number 7

Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers.

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