Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Single- and multiple-dose Once-daily Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Chinese Patients With Type 2 Diabetes Mellitus

Clinical Therapeutics/Volume ], Number ], 2015

Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Single- and Multiple-Dose Once-Daily Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Chinese Patients With Type 2 Diabetes Mellitus Xia Zhao1; Yimin Cui1; Shuai Zhao2; Benjamin Lang3; Uli C. Broedl4; Afshin Salsali5; Sabine Pinnetti3; and Sreeraj Macha5 1

Peking University First Hospital, Beijing, People’s Republic of China; 2Boehringer Ingelheim Corporation, Shanghai, People’s Republic of China; 3Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany; 4Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; and 5Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA ABSTRACT Purpose: The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties and tolerability of the oral once-daily sodium glucose cotransporter 2 inhibitor empagliflozin, given in single and multiple 10 and 25 mg doses in Chinese patients with type 2 diabetes mellitus (T2DM). Methods: In a double-blind, placebo-controlled, parallel-group study, Chinese patients with T2DM were randomly assigned to receive a single dose of empagliflozin 10 or 25 mg or placebo on day 1 and once daily on days 3 to 9. Findings: A total of 24 patients were enrolled (14 men, 10 women; median age, 53.5 years; empagliflozin 10 mg, n ¼ 9; empagliflozin 25 mg, n ¼ 9; and placebo, n ¼ 6). After both single- and multiple-dose administration, empagliflozin 10 and 25 mg were rapidly absorbed, reaching peak plasma concentrations within 1 to 1.5 hours (median), with plasma levels declining biphasically. Empagliflozin exposure increased roughly dose proportionally between 10 and 25 mg. Mean terminal elimination half-life values at steady state were 13.9 and 12.1 hours with empagliflozin 10 and 25 mg, respectively. Mean (SD) changes from baseline in 24-hour urinary glucose excretion (UGE) on day 1 were þ87.7 (22.9) and þ82.8 (18.8) g with empagliflozin 10 and 25 mg, respectively, compared with –1.0 (2.8) g with placebo, and on day 9 were þ95.8 (24.1), þ82.6 (34.8) g with empagliflozin 10 and 25 mg, respectively, compared with –4.1 (6.4) g with placebo. Mean (SD) changes from baseline

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in fasting plasma glucose (FPG) on day 2 were –18.7 (17.2) mg/dL and –25.8 (19.6) mg/dL with empagliflozin 10 and 25 mg, respectively, compared with –4.2 (15.2) mg/dL with placebo, and on day 9, were –25.6 (20.7) mg/dL and –31.4 (26.9) mg/dL with empagliflozin 10 and 25 mg, respectively, compared to –3.7 (7.5) mg/dL with placebo. On day 10, mean changes in weight were –1.1, –1.6, and þ0.5 kg with empagliflozin 10 and 25 mg and placebo, respectively. Overall, empagliflozin 10 and 25 mg had safety profiles similar to that of placebo. There were no reports of hypoglycemia, urinary tract infections, or genital infections. Implications: Results with single and multiple doses of empagliflozin 10 and 25 mg suggest linear pharmacokinetic properties in Chinese patients with T2DM, with a safety profile similar to that of placebo. Empagliflozin treatment was associated with increases in UGE and reductions in FPG compared with placebo. ClinicalTrials.gov identifier: NCT01316341. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: Chinese patients, empagliflozin, fasting plasma glucose, pharmacokinetics, urinary glucose excretion.

Accepted for publication May 1, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.001 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics

INTRODUCTION The prevalence of diabetes continues to increase worldwide.1,2 The prevalence of diabetes in China was estimated at 11.6% in 2013, which may represent up to 113.9 million Chinese adults with diabetes.3 Type 2 diabetes mellitus (T2DM) accounts for 490% of all cases of diabetes,4 but despite the availability of numerous antidiabetic agents, many patients with T2DM, including Chinese patients, fail to achieve optimal glycemic control.5,6 There is a need for welltolerated oral antidiabetic agents with modes of action complementary to those of existing agents, which predominantly rely on insulin-dependent mechanisms to lower glucose.7 Sodium glucose cotransporter 2 (SGLT2), found in the S1/S2 segments of the renal proximal tubule, is involved in  90% of renal glucose reabsorption.8 Inhibitors of SGLT2 reduce renal glucose reabsorption, leading to increased urinary glucose excretion (UGE) and a reduction in plasma glucose9 via a mechanism of action that is not dependent on β-cell function or insulin resistance.10 Empagliflozin is a potent and selective SGLT2 inhibitor11 in development for the treatment of T2DM. Empagliflozin has demonstrated glucoselowering efficacy when administered as monotherapy, as an add-on to metformin alone or metformin with a sulfonylurea, or as an add-on to pioglitazone with or without metformin, and was well tolerated in patients with T2DM.12–17 In addition, empagliflozin reduced weight in patients with T2DM, due to the excretion of calories in the form of glucose in the urine, and reduced blood pressure, consistent with a mild glucose-induced diuretic effect.9,10,12,14,16,17 The pharmacokinetic and pharmacodynamic properties of empagliflozin have been investigated in white and Japanese healthy volunteers18,19 and patients with T2DM.20,21 In patients with T2DM, empagliflozin exposure increased dose proportionally and demonstrated linear pharmacokinetic properties with respect to time after multiple-dose administration. The administration of single doses of empagliflozin led to significant increases in UGE; with multiple dosing, these increases in UGE were maintained, and significant reductions in fasting plasma glucose (FPG) were observed.20,21 Although Japanese patients showed slightly greater empagliflozin exposure compared with white patients, reductions in FPG were similar between the 2 cohorts.20,21 The objectives of this study were to investigate the pharmacokinetic and pharmacodynamic

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properties and tolerability of single and multiple doses of once-daily empagliflozin 10 and 25 mg in Chinese patients with T2DM.

PATIENTS AND METHODS Patients Patients were eligible for participation in the study if they were male or female; of Chinese race; aged 21 to 70 years; had a diagnosis of T2DM; and had been previously treated with diet and exercise alone or with a maximum of 2 oral antidiabetic drugs (except thiazolidinediones), with 1 of the antidiabetic drugs at r50% of its maximum dose, and with doses of all antidiabetic drugs unchanged for Z12 weeks before randomization. Patients were also required to have a body mass index (BMI) of 19 to 40 kg/m2, a glycosylated hemoglobin concentration (HbA1c) of 6.5% to 9.0%, and an estimated glomerular filtration rate (eGFR) of Z80 mL/min/1.73m2 (according to the Modification of Diet in Renal Disease formula) at screening. Key exclusion criteria included uncontrolled hyperglycemia (blood glucose 4240 mg/dL after an overnight fast) at screening; evidence of clinically relevant concomitant disease other than T2DM; hyperlipidemia or medically treated hypertension (o160/o95 mmHg; diuretic use not permitted); QT/corrected QT (QTc) interval prolongation (4450 ms) at screening; a history of risk factors for torsades de pointes or use of a drug that may have influenced the QT/QTc interval within 10 days before study drug administration. Female patients of childbearing potential were required to use adequate contraception. All patients provided written informed consent before study enrollment.

Study Design This randomized, double-blind, placebo-controlled, parallel-group study was undertaken at a single center (Peking University First Hospital, Beijing, China). Eligible patients were randomly assigned, in a 3:3:2 ratio using a validated method involving pseudorandom number generation and seed numbers, to receive empagliflozin 10 or 25 mg or placebo once daily. Patients received a single dose of study drug on day 1 (single-dose period) and continued to receive the same study drug once daily for 7 consecutive days from days 3 to 9 (multiple-dose period). Study medication was taken with 240 mL water at 7 AM after an

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X. Zhao et al. overnight fast. Patients were admitted to the study site and randomized 2 days before the first intake of the study drug (day –2), were discharged on day 13 with home glucose-monitoring equipment to test FPG on days 14 to 21, and attended an end-of-study examination on day 21. Patients were given standardized meals at the study site, each with a predefined energy content (breakfast, 700 kcal; lunch, 800 kcal; supper, 700 kcal) and nutrition content (50% carbohydrates, 30% fat, and 20% protein). All of the patients in each group were given the same meals. The study protocol was reviewed and approved by the institutional review board of Peking University First Hospital, Beijing, China. The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements.

End Points The primary end points of the study were the pharmacokinetic and pharmacodynamic properties of empagliflozin after single- and multiple-dose administration. Pharmacokinetic parameters evaluated in the single-dose period included the maximum concentration in plasma (Cmax), area under the concentration time curve over the time interval from 0 extrapolated to infinity (AUC0–1), time from dosing until maximum plasma concentrations (tmax), terminal half life in plasma (t½), fraction excreted unchanged in the urine over 24 hours (fe0–24) and renal clearance after oral administration (CLR). The same pharmacokinetic parameters of empagliflozin were determined at steady state during the multiple-dose period over a uniform dosing period (τ; Cmax,ss, AUCτ,ss, tmax,ss, t½,ss, fe0–24,ss, and CLR,ss). Pharmacodynamic end points were change from baseline (day –1) in UGE over a 24hour period (UGE0–24) on days 1 (single-dose period) and 9 (multiple-dose period) and change from baseline (day 1) in FPG on day 9. The secondary end point was tolerability, assessed descriptively throughout the study. Adverse events (AEs) were coded using the Medical Dictionary for Drug Regulatory Activities version 14.1, including hypoglycemic events (plasma glucose o70 mg/dL and symptomatic and severe hypoglycemic events) and decreased renal function (a prespecified significant AE, defined as a Z2-fold increase in baseline creatinine value and value above the upper limit of normal).

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Clinical laboratory tests were undertaken at screening, days –1, 1, 2, 6, 7, 8, 9 and at the end-of-study assessment. Vital signs (blood pressure and pulse rate) were measured at screening, days –1, 1, 3 and at the end-of-study assessment. Twelve-lead electrocardiogram (ECG) and physical examinations were performed at screening, days 1, 3 and at the end-of-study assessment. Changes in weight from baseline (day –1) to day 10 and the use of rescue therapy were also assessed as tolerability end points.

Sample Collection and Analyses For pharmacokinetic analysis, venous blood samples (3.0 mL) were drawn into EDTA tubes predose and at 0.16, 0.33, 0.5, 0.66, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose on days 1 and 9. Samples were also drawn 60, 72, and 96 hours postdose on day 9. Within 30 minutes of collection, samples were centrifuged for 10 minutes at 2000 to 4000 g and at 41C to 81C and stored at r–181C until analysis. For FPG assessment, 3 mL of blood was collected in NaF tubes after an overnight fast on day –1, predose on days 1 to 9, and on days 10 to 13. Within 30 minutes of collection, samples were centrifuged for  10 minutes at 2500 g and at 41C and stored at r–181C until analysis. Home glucose-monitoring equipment was used for testing FPG at 7 AM on days 14 to 21. All urine voided on days 1 and 9 was collected over the following sampling periods: 0–2, 2–4, 4–8, 8–12, 12–24, 24–36, and 36–48 hours after study drug administration. All urine voided over sampling periods 48–72 and 72–96 hours postdose on day 9 was collected. Two aliquots of 1.5 mL from each sampling period were stored at r–181C until pharmacokinetic analysis, and 2 aliquots of 1.5 mL were stored at r–201C until analysis of UGE. Additional urine samples over 24 hours were obtained on day –1 to establish baseline UGE. Empagliflozin concentrations in plasma and urine were analyzed using a validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay. Calibration curves were created using weighted quadratic regression, and results were calculated using peak area ratios. An acceptable standard curve was to contain Z75% of the originally specified standard calibrator samples in the final regression set, including Z1 sample each at the upper and lower limits of quantitation. The mean r2 value of the calibration curves was 1.000. For all methods,

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Clinical Therapeutics analysis of quality-control samples demonstrated acceptable precision and accuracy (Z67% of samples were within 15.0% of their respective nominal values, and Z50% of samples at each concentration met the same 15.0% criterion). For quality-control samples of empagliflozin in urine, inter-run precision and accuracy ranged from 3.7% to 8.1%, and from –1.6% to 7.2%, respectively. The lower limits of quantification of empagliflozin were 1.11 nmol/L in plasma and 4.44 nmol/L in urine. Noncompartmental pharmacokinetic parameters were determined using WinNonLinTM software (version 5.2; Pharsight Corporation, Mountain View, California, USA). Cmax and tmax values were determined directly from the plasma concentration–time curves of empagliflozin. The t1/2 was calculated as the quotient of ln(2) and the apparent terminal rate constant (λz), where λz was estimated from a regression of lnC versus time over the terminal log-linear drug-disposition portion of the concentration–time profiles. AUC0–1 was estimated as the sum of AUC over the time interval from 0 to the time of the last quantifiable data point (AUC0–tz), with the extrapolated area given by the quotient of the last measured concentration, and λz where AUC0–tz was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The fraction of the dose excreted unchanged in urine (fe) was determined by the quotient of the sum of drug excreted over all dosing intervals and the dose administered. CLR was determined as the quotient of the amount of drug excreted unchanged in urine over AUC.

Statistical Analysis Pharmacokinetic, pharmacodynamic, and tolerability end points were evaluated using descriptive statistics. Attainment of steady state of empagliflozin was investigated using predose plasma concentrations on days 5 to 9 and repeated-measures analysis of variance (ANOVA) on a logarithmic scale including patient as a fixed effect and time as a repeated effect. Statistical analyses were performed using SAS version 9.2 (SAD Institute, Cary, North Carolina, USA).

RESULTS Demographic and Baseline Characteristics Of 99 patients screened, 24 were randomized and received treatment: 9 received empagliflozin 10 mg, 9 received empagliflozin 25 mg, and 6 received placebo.

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All patients who received empagliflozin were included in the pharmacokinetic analyses. All patients completed the study and were included in the pharmacodynamic and tolerability analyses. Baseline demographics and characteristics were roughly similar across the groups with regard to age (median [range] 53.5 [32–68] years), weight (median [range] 68.0 [50–86] kg), BMI (median [range] 25.5 [19.2–32.4] kg/m2), and HbA1c (mean [SD] 7.67 [0.58]%) (Table I). The mean time since diagnosis of T2DM was greater in patients receiving empagliflozin than in the placebo group (Table I). Mean FPG at baseline was slightly greater in patients receiving empagliflozin than in the placebo group (Table I). Metformin was the most common concomitant antidiabetic medication, used by 15 patients (62.5%) (Table I).

Pharmacokinetic Properties Statistical analysis suggested that empagliflozin plasma concentrations reached steady state by day 6. The pharmacokinetic properties of empagliflozin 10 and 25 mg were similar after single-dose administration and at steady state (Table II and Figure 1). After single- and multiple-dose administration, empagliflozin 10 and 25 mg doses were rapidly absorbed, reaching peak plasma levels between 1 and 1.5 hours after dosing; thereafter, plasma concentrations declined in a biphasic manner, with a rapid distribution phase and slower elimination phase (Table II and Figure 1). Empagliflozin exposure at steady state (Cmax,ss, AUCτ,ss) increased approximately in proportion to the increase in dose. The mean (%CV) steady-state t½ values were 13.9 hours (52.9%) with empagliflozin 10 mg and 12.1 hours (24.1%) with empagliflozin 25 mg (Table II). Consistent with its halflife, up to 17% accumulation of empagliflozin was observed at steady state. The mean (%CV) fraction of empagliflozin dose excreted unchanged in urine at steady state was 20.1 (14.8) % with empagliflozin 10 mg and 21.4 (24.0) % with empagliflozin 25 mg (Table II).

Pharmacodynamic Properties The mean (SD) changes from baseline in UGE0–24 were þ87.7 (22.9), þ82.8 (18.8), and –1.0 (2.8) g after single-dose administration of empagliflozin 10 and 25 mg and placebo, respectively (day 1) (Figure 2). After multiple-dose administration (day 9), the mean (SD) changes from baseline in UGE0–24 were þ95.8 (24.1), þ82.6 (34.8), and –4.1 (6.4) g with empagliflozin 10 and 25 mg and placebo, respectively (Figure 2).

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X. Zhao et al.

Table I. Patient demographics and baseline characteristics. Empagliflozin dose Parameter

10 mg (n ¼ 9)

25 mg (n ¼ 9)

Placebo (n ¼ 6)

Age, median (range), y Sex, no. (%) Male Female BMI, median (range), kg/m2 Weight, median (range), kg Time since diagnosis of T2DM, mean (SD), y HbA1c, mean (SD), % FPG, mean (SD), mg/dL Antidiabetic medication, no. (%) Metformin Sulfonylurea Acarbose

53.0 (44–68)

56.0 (32–64)

51.0 (43–65)

7 2 26.5 74.0 10.7 7.39 166.67

(77.8) (22.2) (19.2–30.5) (51–85) (5.95) (0.51) (28.11)

8 (88.9) 1 (11.1) 0

3 6 24.7 67.0 7.64 7.91 160.56

(33.3) (66.7) (20.8–26.5) (50–71) (4.35) (0.52) (24.81)

5 (55.6) 4 (44.4) 3 (33.3)

4 2 25.5 72.0 2.96 7.72 148.17

(66.7) (33.3) (21.5–32.4) (60–86) (3.75) (0.67) (22.34)

2 (33.3) 1 (16.7) 0

Total (N ¼ 24) 53.5 (32–68) 14 10 25.5 68.0 7.61 7.67 159.75

(58.3) (41.7) (19.2–32.4) (50–86) (5.59) (0.58) (25.52)

15 (62.5) 6 (25.0) 3 (12.5)

BMI ¼ body mass index; FPG ¼ fasting plasma glucose; HbA1c ¼ glycosylated hemoglobin; T2DM ¼ type 2 diabetes mellitus.

Table II. Pharmacokinetic properties of single and multiple doses of 10 mg and 25 mg empagliflozin once daily in Chinese patients with Type 2 diabetes. Single-dose period

Parameter AUC0-∞, nmol  h/L, mean (%CV) Cmax, nmoI/L, mean (%CV) tmax, h, median (range) t½, h, mean (%CV) fe0-24, %, mean (%CV) CLR,0-48, mL/min, mean (%CV)

Empagliflozin 10 mg (n ¼ 9)

Multiple dose period Empagliflozin 25 mg (n ¼ 9)

Parameter

Empagliflozin 10 mg (n ¼ 9)

Empagliflozin 25 mg (n ¼ 9)

AUCt,ss,nmol  h/L, 2680 (16.1) 7670 (21.7) mean (%CV) 439 (14.0) 1130 (28.2) Cmax,ss,nmol/L, 505 (25.0) 1310 (36.1) mean (%CV) 1.0 (0.7–2.0) 1.5 (1.0–3.0) tmax,ss,h, 1.0 (0.7–2.0) 1.5 (1.0–2.5) median (range) 9.62 (29.7) 10.7(21.6) t½,ss, h, 13.9 (52.9) 12.1 (24.1) mean (%CV) 18.5 (17.6) 18.4 (23.8) fe0-24,ss, %, 20.1 (14.8) 21.4 (24.0) mean (%CV) 29.5 (21.6) 26.7 (31.5) CLR,ss, mL/min, 28.1 (15.4) 27.2 (34.1) mean (%CV)

2580 (12.4)

7450 (26.3)

AUC0-∞ ¼ area under the plasma concentration-time curve from time 0 extrapolated to infinity; CV ¼ coefficient of variation; AUCt,ss ¼ AUC at steady state over a uniform dosing interval; Cmax ¼ maximum measured plasma concentration; ss ¼ steady state; tmax ¼ time from dosing to Cmax; t½ ¼ terminal half-life; fe0-24 ¼ fraction of empagliflozin excreted unchanged in the urine over 24 hours; CLR,0-48 ¼ renal clearance of empagliflozin over 48 hours after oral administration; CLR,ss ¼ renal clearance of empagliflozin at steady state.

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Empagliflozin plasma concentration (nmol/L)

Clinical Therapeutics

1600 1400 1200 Empagliflozin 10 mg 1000 Empagliflozin 25 mg

800 600 400 200 0 0

24

192

48

216

240

264

Empagliflozin plasma concentration (nmol/L)

Time (hours)

10000 Empagliflozin 10 mg 1000

Empagliflozin 25 mg

100

10

1 0

24

192

48

216

240

264

Time (hours)

Figure 1. Linear (A) and semilogarithm (B) scales of arithmetic mean (SD) plasma concentration-time profile of empagliflozin after the administration of single-dose and multiple doses of empagliflozin 10 and 25 mg in Chinese patients with type 2 diabetes mellitus.

The mean (SD) changes from baseline in FPG were –18.7 (17.2), –25.8 (19.6), and –4.2 (15.2) mg/dL after single-dose administration of empagliflozin 10 and 25 mg and placebo, respectively (day 2), and –25.6 (20.7), –31.4 (26.9), and –3.7 (7.5) mg/dL, respectively, after multiple doses (day 9) (Figure 3).

Tolerability The mean changes from baseline to day 10 in weight, assessed as a tolerability end point, were –1.1 (0.9),

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–1.6 (1.1), and þ0.5 (1.0) kg with empagliflozin 10 and 25 mg and placebo, respectively. Both doses of empagliflozin were well tolerated. In total, 9 patients (37.5%) reported Z1 AE: 4 patients (44.4%) in the empagliflozin 10 mg group, 2 patients (22.2%) in the empagliflozin 25 mg group, and 3 patients (50.0%) in the placebo group (Table III). A total of 14 AEs were reported among these 9 patients. All of the AEs were considered by the investigator to have been of mild intensity and occurred during the multiple-dose period. The most

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X. Zhao et al. Baseline mean (Day –1)

18.3

10.6

3.8

Mean (SD) change from baseline in UGE (g)

140 95.8

120

87.7

82.6

Day 1 Day 9

82.8

100 80 60 40 20 0 –20

–1.0

–4.1

–40 –60

Placebo (n=6)

Empagliflozin 10 mg (n=9)

Empagliflozin 25 mg (n=9)

Figure 2. Mean change from baseline in urinary glucose excretion (UGE) after single (Day 1) and multiple (Day 9) doses of empagliflozin 10 and 25 mg in Chinese patients with type 2 diabetes mellitus.

frequently reported AEs were toothache (reported in 2 patients on empagliflozin 10 mg, 1 patient on empagliflozin 25 mg, and 1 patient on placebo), pruritus (reported in 2 patients on empagliflozin 10 mg and 1 patient on placebo), and diarrhea (reported in 1 patient on empagliflozin 10 mg and 1 patient on placebo). Of the 14 AEs reported, 5 were considered by the investigators to have been treatment related: 2 cases of pruritus and 1 case of toothache in the empagliflozin 10 mg group, and 1 case each of pruritus and abnormal eosinophil count in the placebo group. None of the patients discontinued treatment due to an AE. None of the patients had hypoglycemia or required rescue therapy. There were no reports of urinary tract or genital infections, or decreased renal function AE. No clinically relevant changes in physical examination, vital signs (blood pressure and pulse rate), ECG or laboratory test results, were seen.

DISCUSSION In these Chinese patients with T2DM, empagliflozin demonstrated dose-dependent pharmacokinetic properties after the administration of single and multiple doses of 10 and 25 mg. Similar to observations in studies in white patients,20 empagliflozin was rapidly absorbed and

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showed biphasic decline. Pharmacokinetic properties were similar after single-dose administration and at steady state, suggesting linear pharmacokinetic properties. Increases in exposure to empagliflozin were roughly proportional with the increase in dose from 10 to 25 mg at steady state. Empagliflozin exposure was 1.4- to 1.9-fold greater in the Chinese patients with T2DM in this trial compared with that reported in white patients.20 Slightly greater exposure to empagliflozin (1.4- to 1.5-fold) in Japanese patients relative to white patients has also been reported.21 These increases may be attributed to differences in BMI, as the median BMI was 29.5 to 30.6 kg/m2 in white patients,20 compared with 25.5 kg/m2 in Chinese patients with T2DM in this trial and 24.3 kg/m2 Japanese patients,21 or differences in weight as the median weight was 89.3–92.4 kg in white patients20 compared with 68.0 kg in Chinese patients in this trial and in Japanese patients21. However, as these increases in empagliflozin exposure are o2-fold and based on the safety profile established in Phase II/III studies, they are not considered to be clinically relevant. As expected, due to the mechanism of action of empagliflozin,9 single and multiple doses of empagliflozin 10 and 25 mg increased UGE from baseline in these Chinese patients with T2DM.

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Clinical Therapeutics Baseline mean (Day 1)

148.17

166.67

160.56

Mean (SD) change from baseline in FPG (mg/dL)

20

Day 2 Day 9

10 0 –10 –3.7 –20

–4.2

–30 –18.7

–40 –50

–25.8

–25.6

–60 Placebo (n=6)

–31.4 Empagliflozin 25 mg (n=9)

Empagliflozin 10 mg (n=9)

Figure 3. Mean change from baseline in fasting plasma glucose (FPG) after single (Day 2) and multiple (Day 9) doses of empagliflozin 10 and 25 mg in Chinese patients with type 2 diabetes mellitus.

Increased UGE led to declines in FPG immediately after single-dose administration of empagliflozin, and these effects appeared to be maintained over the treatment period with multiple 10 and 25 mg doses of empagliflozin. The effects of empagliflozin on UGE and FPG in Chinese patients with T2DM are consistent with data seen for white and Japanese patients with T2DM.20,21 In addition to effects on glycemic control, treatment with empagliflozin for 10 days was associated with decreases in weight of 1.1 to 1.6 kg in this study. Four

week’s treatment with empagliflozin in white patients with T2DM led to decreases in weight of 1.5 to 2.6 kg.20 Dose-dependent increases in exposure have been observed with the SGLT2 inhibitor dapagliflozin, with no clinically relevant effect of race, and UGE has been associated with dose-related decreases in plasma glucose parameters in patients with T2DM.22 The pharmacokinetic and pharmacodynamic properties of dapagliflozin in healthy Chinese subjects were similar to those observed in healthy non-Chinese subjects.23

Table III. Summary of Chinese patients with Type 2 diabetes with adverse advents (AEs). Empagliflozin dose n (%) Treated Patients Patients Patients Patients Patients Patients Patients

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10 mg with with with with with with with

any AE severe AEs investigator defined drug-related AEs AEs leading to discontinuation hypoglycemic events pre-specified significant AEs serious AEs

4 0 2 0 0 0 0

9 (44.4) (0.0) (22.2) (0.0) (0.0) (0.0) (0.0)

25 mg 2 0 0 0 0 0 0

9 (22.2) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)

Placebo 3 0 1 0 0 0 0

6 (50.0) (0.0) (16.7) (0.0) (0.0) (0.0) (0.0)

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X. Zhao et al. Dose-dependent increases in exposure have been reported with the SGLT2 inhibitor canagliflozin, and the pharmacodynamic effects were dose- and exposure-dependent in patients with T2DM.24 Both doses of empagliflozin were well tolerated. All AEs were of mild intensity, there were no serious AEs reported, and none of the patients discontinued due to an AE. The efficacy and tolerability of empagliflozin as a treatment of T2DM will be evaluated further in the large-scale, global, Phase III clinical trial program. Limitations of this study included the small number of patients treated and that the study was not powered to evaluate differences in pharmacodynamic properties between empagliflozin and placebo.

CONCLUSIONS The similarities in the single-dose and steady-state pharmacokinetic properties of empagliflozin suggest linear pharmacokinetics in Chinese patients with T2DM. Empagliflozin treatment resulted in increases in UGE and improvements in glycemic control, consistent with findings reported in white and Japanese patients, and was well tolerated.

ACKNOWLEDGMENTS The authors thank Lois Rowland for coordinating the bioanalytical analysis, Jeanette Garcia for undertaking the non-compartmental pharmacokinetic analysis, and Christina Gondolfi for providing the pharmacokinetic and pharmacodynamic sample logistics. Medical writing assistance was provided by Clare Ryles and Elizabeth Ng, Fleishman-Hillard Group Ltd, during the preparation of the manuscript. The authors meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors. Drs X. Zhao, Y. Cui, S. Zhao, and S. Macha made substantial contributions to the study conception and design and were involved in the acquisition of the data. All of the authors were involved in the analysis and interpretation of the data and in drafting the article and/or revising it critically for important intellectual content. The authors were fully involved in all content and editorial decisions, were involved in all stages of manuscript development, and approved the final version.

CONFLICTS OF INTEREST This study was sponsored by Boehringer Ingelheim. S. Zhao, B. Lang, U.C. Broedl, A. Salsali and S. Pinnetti

] 2015

are employees of Boehringer Ingelheim. S. Macha was an employee of Boehringer Ingelheim at the time the study was conducted and when drafting the article. X. Zhao and Y. Cui have no conflicts of interest to disclose. Medical writing assistance was financially supported by Boehringer Ingelheim.

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Address correspondence to: Yimin Cui, Xishiku Street, No. 8 Xicheng District, Beijing 100034, People’s Republic of China. E-mail: cuiymzy@ 126.com

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