Clinical Therapeutics/Volume 36, Number 11, 2014

Effect of Renal Impairment on the Pharmacokinetics,Pharmacodynamics, and Safety of Empagliflozin, a SodiumGlucose Cotransporter 2 Inhibitor, in Japanese Patients WithType 2 Diabetes Mellitus

Akiko Sarashina1; Kohjiro Ueki2,3,4; Tomohiro Sasaki1; Yuko Tanaka5; Kazuki Koiwai5;Wataru Sakamoto5; Hans J. Woerle6; Afshin Salsali6; Uli C. Broedl6; and Sreeraj Macha7

1Nippon Boehringer Ingelheim Co Ltd, Hyogo, Japan; 2Department of Molecular Sciences on Diabetes,Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 3Department of Diabetes andMetabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 4Department ofMolecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for GlobalHealth and Medicine, Tokyo, Japan; 5Nippon Boehringer Ingelheim Co Ltd, Tokyo, Japan; 6BoehringerIngelheim GmbH & Co KG, Ingelheim, Germany; and 7Boehringer Ingelheim Pharmaceuticals Inc,Ridgefield, Connecticut

Accepted for publication August 1, 2014.http://dx.doi.org/10.1016/j.clinthera.2014.08.0010149-2918/$ - see front matter

& 2014 Elsevier HS Journals, Inc. All rights reserved.

ABSTRACT

Purpose: The purpose of this study was to assess theeffect of renal impairment on the pharmacokinetic,pharmacodynamic, and safety profiles of empagliflozin,a sodium glucose cotransporter 2 (SGLT2) inhibitor, inJapanese patients with type 2 diabetes mellitus (T2DM).

Methods: In an open-label, parallel-group study, 32Japanese patients with T2DM and different degrees ofrenal function (n ¼ 8 per renal function category:normal renal function, estimated glomerular filtrationrate [eGFR; Japanese equation] Z90 mL/min/1.73 m2;mild renal impairment, eGFR of 60–o90 mL/min/1.73 m2; moderate renal impairment, eGFR of 30–o60 mL/min/1.73 m2; and severe renal impairment,eGFR of 15–o30 mL/min/1.73 m2) received a single25 mg dose of empagliflozin.

Findings: Empagliflozin exposure increased withincreasing renal impairment. Maximum empagliflo-zin plasma concentrations were similar among allrenal function groups. Adjusted geometric meanratios for extent of exposure (AUC0–1) to empagli-flozin versus normal renal function were 128.8%(95% CI, 106.0–156.6%), 143.8% (95% CI, 118.3–174.8%), and 152.3% (95% CI, 125.3–185.2%) forpatients with mild, moderate, and severe renal im-pairment, respectively. Decreases in renal clearanceof empagliflozin correlated with eGFR. Urinaryglucose excretion decreased with increasing renal

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impairment and correlated with eGFR (adjustedmean [SE] change from baseline: 75.0 [4.84] g,62.6 [5.75] g, 57.9 [4.86] g, and 23.7 [5.24] g forpatients with normal renal function and mild, mod-erate, and severe renal impairment, respectively).Only 2 patients (6%) had adverse events; bothwere mild.

Implications: Pharmacokinetic data suggest that nodose adjustment of empagliflozin is necessary in Japa-nese patients with T2DM and renal impairment be-cause increases in exposure were o2-fold. Urinaryglucose excretion decreased with increasing renal im-pairment. ClinicalTrials.gov identifier: NCT01581658.(Clin Ther. 2014;36:1606–1615) & 2014 Elsevier HSJournals, Inc. All rights reserved.

Key words: empagliflozin, Japanese patients, phar-macodynamics, pharmacokinetics, renal impairment,SGLT2 inhibitor.

INTRODUCTIONThe number of patients with diabetes worldwidecontinues to increase, with Japan having the 10th

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A. Sarashina et al.

highest incidence of the disease at an estimated7.2 million cases of diabetes.1 Because most of thesepatients have type 2 diabetes mellitus (T2DM), theJapan Ministry of Health, Labour and Welfare hasidentified T2DM as a healthcare priority.2

Up to 67% of Japanese patients with T2DM alsohave impaired renal function3,4 or chronic kidney disease(CKD) stages 2 to 5 according to the recent KidneyDisease: Improving Global Outcomes guidelines.5 Indeed,10% to 15% of patients with T2DM have moderaterenal impairment or worse (CKD stages 3–5).3,4 Diabeticnephropathy in patients with T2DM is the leading causeof end-stage renal disease.6 The number of patients withdiabetic nephropathy in Japan has increased yearly from1983 to 2010, with 44% of patients starting dialysis inJapan in 2010 having diabetic nephropathy.7 Impairedrenal function can affect the pharmacokinetic propertiesof drugs that are eliminated primarily through renalexcretory mechanisms, which can affect their safetyand pharmacodynamic profiles and necessitate doseadjustments.8

Empagliflozin, a potent and selective sodium glu-cose cotransporter 2 (SGLT2) inhibitor,9 has beenapproved in the US and Europe for the treatment ofT2DM. SGLT2 is responsible for reabsorption ofmost glucose filtered daily by the glomerulus backinto the circulation.10 By blocking SGLT2, empag-liflozin increases urinary glucose excretion (UGE) andimproves plasma glucose levels, as seen in both whiteand Japanese patients with T2DM.11–13 Empagliflozin israpidly absorbed with dose-proportional increases inexposure in healthy individuals (both white and Japa-nese).14,15 Single oral doses of empagliflozin (0.5–800mg) exhibit linear pharmacokinetic properties in healthyindividuals.14 Empagliflozin undergoes limited meta-bolism; no major metabolites of empagliflozin havebeen detected in plasma (data on file). Empagliflozin isprimarily excreted unchanged in urine and feces. Inhealthy Japanese subjects, approximately 20% to 30%of the dose of empagliflozin is excreted unchanged in theurine.15 Thus, renal impairment is unlikely to affect themetabolism of empagliflozin but may affect its excretion.Because the mechanism of action of empagliflozin isdependent on the filtered glucose load in the glomeruli,and hence on the glomerular filtration rate (GFR), theincrease in UGE is inversely associated with the degreeof renal function in white patients with renalimpairment.16 This study was undertaken to assess theeffect of renal impairment on the pharmacokinetic,

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pharmacodynamic, and safety profiles of a single doseof empagliflozin 25 mg, the maximum dose beinginvestigated in Phase III studies, in Japanese patientswith T2DM.

PATIENTS AND METHODSPatients

Japanese patients (male or female) with T2DM andan estimated GFR (eGFR; using the Japanese GFRestimation equation recommended by the JapaneseSociety of Nephrology17) of Z90 mL/min/1.73 m2

(normal renal function; CKD stage 1), 60 to o90 mL/min/1.73 m2 (mild renal impairment; CKD stage 2), 30to o60 mL/min/1.73 m2 (moderate renal impairment;CKD stage 3), or 15 to o30 mL/min/1.73 m2 (severerenal impairment; CKD stage 4) were eligible forinclusion in this study. Patients were required to beZ20 and r75 years of age, have a body mass index(BMI) Z18 and r34 kg/m2, body weight Z45 kg, anda glycosylated hemoglobin (HbA1c) Z6.5% atscreening. Concomitant medication for the treatmentof T2DM, including insulin, or for the treatment ofconcomitant diseases was permitted, except formedications known to induce P-glycoprotein. Theregimen for concomitant medications had to have beenunchanged for Z4 weeks before study drug adminis-tration. Patients were excluded from the study if theyhad significant disease other than T2DM and renalimpairment, including moderate or severe hepatic im-pairment. Other key exclusion criteria included gastro-intestinal tract surgery; diseases of the central nervoussystem; psychiatric or neurologic disorders; chronic orrelevant acute infections; history of relevant orthostatichypotension, fainting spells, blackouts, or allergy orhypersensitivity; clinically relevant laboratory abnor-malities (except parameters related to renal impair-ment); intake of drugs known to induce P-glyco-protein within 3 weeks before study drug administra-tion; or participation in another clinical trial within 30days before study drug administration. Women of child-bearing potential were required to use adequate contra-ception. Dialysis was not an exclusion criterion.

Study DesignThis was an open-label, parallel-group study con-

ducted in a single center in Japan. Patients werescreened within 21 days of study drug administration.If the interval between screening and study drugadministration was 47 days, eGFR was recalculated.

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Eligible patients received a single dose of empagliflozin25 mg (Boehringer Ingelheim Pharma GmbH & CoKG, Ingelheim, Germany). Patients were admitted tothe study site the day before study drug administration(day �1), received the study drug (with 150 mL ofwater) at 9 am the following morning after an over-night fast (day 1), and were closely supervisedin-house until discharged (day 5). Concomitant medi-cation was not permitted from 1 hour before until4 hours after study drug administration. Patientsattended a follow-up visit within 10 days of discharge.Investigators aimed to recruit 32 Japanese patients withT2DM: 8 patients in each renal function category.

The study protocol was approved by the Institu-tional Review Board of Applied Bio-PharmatechKurume Clinical Pharmacology Clinic, Fukuoka,Japan. The study was conducted in accordance withthe principles of the Declaration of Helsinki, theInternational Conference on Harmonization Harmon-ized Tripartite Guideline for Good Clinical Practice,and Japanese Good Clinical Practice regulations. Allpatients provided written informed consent beforestudy participation.

Sample Collection and AnalysesFor pharmacokinetic analysis, venous blood samples

(3 mL) were drawn into ethylenediaminetetraaceticacid (EDTA) tubes before dosing and 0.33, 0.66, 1,1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, and 96hours after dosing. For the analysis of plasma proteinbinding of empagliflozin, 8 mL of blood was collected1.5 hours after empagliflozin dosing. Blood sampleswere centrifuged within 30 minutes of collection forapproximately 10 minutes at 2000 to 4000g and 41Cto 81C and stored at �201C until analysis.

All urine voided was collected in the 24 hours beforedosing and during the sampling periods 0 to 4, 4 to 8, 8to 12, 12 to 24, 24 to 36, 36 to 48, 48 to 72, and 72 to96 hours after dosing. The �24 to 0 hour sample wasused for determination of baseline UGE, predoseconcentration of empagliflozin, and urine creatinine.Samples were stored at �201C or below until analysis.

Empagliflozin concentrations in plasma and urinewere analyzed using a validated high performanceliquid chromatography-tandem mass spectrometry(HPLC-MS/MS) assay with a solid-phase–supportedliquid extraction process. The lower limits of quantifi-cation for empagliflozin were 1.11 nmol/L in plasmaand 4.44 nmol/L in urine. The mean precision for

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quantification of empagliflozin in plasma (608 samples)and urine (288 samples) was r6.6% and r5.7%,respectively, and the accuracy of standard calibratorsamples was �4% in plasma and �3.5% in urine.

Non-compartmental pharmacokinetic parameterswere determined using WinNonLin™ software, ver-sion 5.2 (Pharsight Corporation, Mountain View,California). Maximum plasma concentration (Cmax)and time to Cmax (tmax) values were determineddirectly from the plasma concentration-time curvesfor empagliflozin. The terminal elimination half-life(t½) was calculated as the quotient of ln(2) and theapparent terminal rate constant (λz), where λz wasestimated from a regression of ln(C) versus time overthe terminal log-linear drug disposition portion of theconcentration-time profiles. AUC0-–1 was estimatedas the sum of the AUC during the interval 0 to thetime of the last quantifiable data point with theextrapolated area given by the quotient of the lastmeasured concentration and λz. The fraction of doseexcreted unchanged (fe) was calculated as the quotientof the sum of drug excreted during all observedintervals and the dose administered, and renal clear-ance (CLR) as the quotient of the amount of drugexcreted unchanged in the urine over AUC. Proteinbinding of empagliflozin was determined using equi-librium dialysis. UGE was calculated as glucose con-centration (mg/dl) � urine volume (dl).

EndpointsThe primary pharmacokinetic endpoints were the

AUC0–1 and Cmax of empagliflozin, from which theeffect of renal impairment on the pharmacokineticproperties of empagliflozin was determined. Otherpharmacokinetic end points included tmax, t½, fractionof dose excreted unchanged in the urine from 0 to 96hours (fe0-96), CLR during the interval t1 to t2 hours,and plasma protein binding of empagliflozin.

The primary pharmacodynamic end point was thechange from baseline in UGE during 24 hours (UGE0–24).The safety evaluation was based on adverse events(AEs), vital signs, and clinical laboratory tests. AEswere monitored throughout the study and coded usingthe Medical Dictionary for Drug Regulatory Activ-ities, version 15.1. Vital signs (blood pressure andpulse) were measured at screening, on admission tothe study site (day �1), before dosing on day 1, on themornings of days 2 to 5, and at follow-up. Clinicallaboratory tests (blood samples collected after a

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A. Sarashina et al.

10-hour fast) were conducted at screening, on days�1, 2, and 5, and at follow-up, if there were anyclinically significant laboratory findings observedon day 5.

Statistical AnalysisStatistical analyses were undertaken using data from

all patients who received the study drug (treated set).The relative bioavailability of empagliflozin in patientswith normal renal function (reference: R) comparedwith patients with different degrees of renal impairment(test: T1-T3) was investigated by determining each T/Rratio of AUC0–1 and Cmax. The primary pharmacoki-netic parameters AUC0–1 and Cmax were log-transformed (natural logarithm) before fitting an AN-OVA model that included a fixed effect for renalfunction (normal, mild impairment, moderate impair-ment, or severe impairment). The geometric mean ratio(GMR) between each renal function group and patientswith normal renal function was estimated using thedifference in the corresponding least square means, and2-sided 90% CIs based on the t-distribution werecalculated. These quantities were back-transformed tothe original scale to provide the point estimate and90% CI. Descriptive statistics were calculated forplasma concentrations and all other pharmacokineticparameters for each renal function category and forsafety endpoints. Change from baseline in UGE0–24

after study drug administration was determined byANCOVA, including renal function category as a fixedeffect and baseline UGE (0-24 hours before drugadministration) as a continuous covariate.

Table I. Demographic and baseline characteristics (trea

Characteristic

Normal Renal

Function

(n ¼ 8)

Ren

Mild

(n ¼ 8)

Male, No. (%) 4 (50.0) 5 (62.5)Age, y 66.5 (62–71) 68.0 (60–74) 66Weight, kg 56.90 (54.0–77.0) 64.65 (49.6–73.5) 69.BMI, kg/m2 24.63 (18.3–26.6) 24.08 (20.1–25.9) 24.HbA1c, % 6.98 (6.5–9.1) 7.34 (6.7–9.6) 7.

BMI = body mass index; HbA1c = glycosylated hemoglobin.*Data are presented as median (range) unless otherwise indicat

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RESULTSPatients

In total, 32 Japanese patients with T2DM partici-pated in this study, with 8 patients in each renalfunction category (normal renal function, mild impair-ment, moderate impairment, and severe impairment).All 32 patients completed the study. Demographic andbaseline characteristics are given in Table I. Nopatients were receiving dialysis.

Pharmacokinetic PropertiesAfter rapid absorption, empagliflozin plasma con-

centrations decreased in a biphasic manner with arapid distribution phase followed by a slower elimina-tion phase in patients in all renal function groups(Figure 1A). The peak levels (Cmax) of empagliflozinwere similar for patients in all renal function groups(Table II and Figure 1B), as was tmax (Table II). The t½of empagliflozin was slightly prolonged in patients withmoderate renal impairment (Table II). The extent ofexposure (AUC0–1) to empagliflozin increased with in-creasing renal impairment (Table II and Figure 1C) andmoderately correlated with eGFR (Figure 2A), whereasthe CLR of empagliflozin decreased with increasingrenal impairment (Table II) and correlated with eGFR(Figure 2B). The mean fe0-96 of empagliflozin decreasedwith increasing renal impairment (Table II).

Relative BioavailabilityThe Cmax of empagliflozin was similar in patients

with renal impairment compared with those withnormal renal function (Table III and Figure 1B).

ted set).

al Impairment

Total

(N ¼ 32)

Moderate

(n ¼ 8)

Severe

(n ¼ 8)

8 (100.0) 6 (75.0) 23 (71.9).0 (59–75) 60.0 (49–72) 67.0 (49–75)20 (59.4–74.3) 61.35 (45.1–75.2) 63.35 (45.1–77.0)63 (23.0–28.6) 22.99 (20.6–28.7) 24.50 (18.3–28.7)39 (6.6–8.8) 6.78 (6.5–7.7) 7.08 (6.5–9.6)

ed.

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B

C

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10 12 24 36 48 60 72 84 96

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Mild

Moderate

Severe

500

Empa

glifl

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sma

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/L)

00 12 24 36 48 60

Time, h72 84 96

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ax o

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ifloz

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Mean

Individual data

Geometric mean

Mean

Figure 1. Exposure to a single, oral, 25 mg dose of empagliflozin in Japanese patients with type 2 diabetesmellitus and normal or impaired renal function (n ¼ 8 per group). Mean plasma concentration-timeprofile (A; insert semilog plot), Cmax (B), and AUC0–1 (C).

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Table II. Pharmacokinetics and pharmacodynamic parameters of empagliflozin after administration of asingle, oral, 25 mg dose in Japanese patients with type 2 diabetes mellitus.*

Renal Impairment

Parameter

Normal Renal

Function (n ¼ 8) Mild (n ¼ 8) Moderate (n ¼ 8) Severe (n ¼ 8)

Pharmacokinetic Parameters

AUC0–1, nmol � h/L 7560 (14.9) 9730 (14.7) 10,800 (9.18) 12,200 (40.1)Cmax, nmol/L 1070 (18.1) 1030 (34.4) 1000 (26.4) 1070 (42.3)tmax, median (range), h 2.50 (1.00–2.50) 2.50 (1.00–4.00) 2.50 (0.667– 6.00) 3.25 (1.00–6.00)t½, h 19.1 (56.7) 18.4 (33.7) 24.3 (39.2) 19.4 (44.7)fe0–96,% 19.1 (16.5)† 16.8 (19.7)† 14.6 (27.7) 5.41 (45.3)‡

CLR,0–96, mL/min 24.1 (25.3)† 16.4 (23.8)† 13.2 (33.3) 4.45 (47.4)‡

Pharmacodynamic Properties

UGE0–24, baseline, g 2.79 (2.11) 4.77 (3.02)† 1.59 (0.774) 0.953 (0.569)†

UGE0–24, g 78.0 (7.63) 66.5 (7.08)† 58.7 (4.61) 21.7 (4.09)Change from baseline, g§ 75.0 (4.84) 62.6 (5.75)‡ 57.9 (4.86) 23.7 (5.24)†

AUC0-∞ = area under the plasma concentration-time curve from time 0 extrapolated to infinity; Cmax = maximum plasmaconcentration; tmax = time from dosing to Cmax; t½ = terminal half-life; fe0-96 = fraction of empagliflozin excretedunchanged in the urine over 96h; CLR,0-96 = renal clearance of empagliflozin over 96 h; UGE0-24 = urinary glucose excretionover a 24-h period.*Pharmacokinetic values are mean (coefficient of variation [%]) and pharmacodynamic values are mean (SE), unlessotherwise stated.

†n ¼ 7.‡n ¼ 6.§Mean (SE) adjusted for baseline UGE and renal function.

A. Sarashina et al.

Increases of approximately 29%, 44%, and 52% wereseen for AUC0–1 (adjusted geometric mean ratio)in patients with mild, moderate, and severe renalimpairment, respectively, compared with patientswith normal renal function (Table III and Figure 1C).

Protein BindingMean (SD) protein binding of empagliflozin 1.5

hour after administration was 85.5 (1.3)%, 85.1(1.0)%, and 81.4 (3.0)% in patients with T2DMand mild, moderate, and severe renal impairment,respectively, and 84.7 (1.4)% in patients with T2DMand normal renal function.

Pharmacodynamic PropertiesAdjusted mean change from baseline in UGE0–24

associated with empagliflozin decreased with increas-ing renal impairment, from approximately 75 g inpatients with normal renal function to approximately

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24 g in patients with severe renal impairment (Table IIand Figure 3). The decrease in UGE0–24 correlatedwith eGFR (Figure 2C) and filtered glucose (calculatedbased on eGFR and plasma glucose) (Figure 2D).

Safety Profile and TolerabilityIn total, 2 (6%) patients with T2DM had AEs after

a single dose of empagliflozin 25 mg, both of whomhad moderate renal impairment (25%). Both AEs weremild. One patient had decreased appetite, which wasnot considered drug related by the investigator, and theother had abdominal distension, which was considereddrug related. Both patients recovered without treat-ment. There were no clinically relevant changes inlaboratory parameters or vital signs during the study.

DISCUSSIONThis study was undertaken to determine the effect ofdegrees of renal impairment on the pharmacokinetic,

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Spearman correlation coefficient: –0.50725000

20000

15000

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00 20 40 60 80 100 120 140 160 180

eGFR (mL/min/1.73 m2)

AU

C0–

00 o

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pagl

ifloz

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mol

.h/L

)

140

120

100

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60

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00 20 40 60 80

eGFR (mL/min/1.73 m2)

Spearman correlation coefficient: 0.729

UG

E 0–2

4 (g

)

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Filtered glucose (g/h)

UG

E 0–2

4 (g

)

20 25 30

50

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0

eGFR (mL/min/1.73 m2)

Spearman correlation coefficient: 0.873

CL R

,0-2

4 of

Em

pagl

ifloz

in(m

l/m

in)

0 20 40 60 80 100 120 140 160 180

A B

C D

Figure 2. Estimated glomerular filtration rate (eGFR) versus AUC0–1 (n ¼ 32) (A), renal clearance ofempagliflozin during 96 hours (CLR,0–24) (n ¼ 31) (B), urinary glucose excretion during a 24-hourperiod (UGE0–24) (n ¼ 31) (C), and filtered glucose versus UGE0–24 (n ¼ 31) (D) afteradministration of a single, oral, 25 mg dose of empagliflozin in Japanese patients with type 2diabetes mellitus and normal or impaired renal function.

Table III. Relative bioavailability of empagliflozin (25 mg single dose) in Japanese patients with type 2 diabetesmellitus and impaired renal function compared with Japanese patients with type 2 diabetes mellitusand normal renal function (n ¼ 8 per group).

Renal Impairment Group Parameter

Adjusted GMR(Renal Impaired/Normal Group)

(90% CI), %

Mild AUC0–1 128.8 (106.0–156.6)Cmax 93.5 (72.2–121.0)

Moderate AUC0–1 143.8 (118.3–174.8)Cmax 92.2 (71.2–119.3)

Severe AUC0–1 152.3 (125.3–185.2)Cmax 94.0 (72.6–121.7)

GMR = geometric mean ratio (impaired renal function: normal renal function); CI = confidence intervals; AUC0-∞ = areaunder the plasma concentration-time curve from time 0 extrapolated to infinity; Cmax = maximum plasma concentration.

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Normal renal function250

200

150

100

50

024 48

Time (h)

Cum

ulat

ive

Am

ount

of G

luco

seEx

cret

ed in

Urin

e (g

)

72 960

Mild renal impairment

Moderate renal impairment

Servere renal impairment

Figure 3. Mean cumulative amounts of urinaryglucose excretion after administrationof a single 25 mg dose of empagli-flozin in Japanese patients with type 2diabetes mellitus and normal or im-paired renal function (n ¼ 8 per group).

A. Sarashina et al.

pharmacodynamic, and safety profiles of a single doseof empagliflozin in Japanese patients with T2DM. Theextent of exposure (AUC0–1) to empagliflozin 25 mgincreased with increasing renal impairment inJapanese patients with T2DM. The AUC0–1 wasincreased by 29%, 44%, and 52% in patients withmild, moderate, and severe renal impairment, respec-tively, compared with patients with normal renalfunction, and the upper limits of the 90% CIs forAUC0–1 were outside the standard bioequivalenceboundaries (80%–125%) in all renal impairmentgroups. Although the extent of exposure increased withincreasing renal impairment, renal impairment had noeffect on Cmax or tmax. The mean t½ of empagliflozinwas slightly prolonged in patients with moderate renalimpairment, but this was not observed in patients withsevere renal impairment. No marked effect of renalimpairment on protein binding of empagliflozin wasobserved, except for a slight decrease in patients withsevere renal impairment compared with those withnormal renal function (81.4% vs 84.7% at 1.5 hoursafter dosing). Because renal clearance of empagliflozindecreased with an increase in renal impairment, thiswould primarily account for the observed increase inempagliflozin exposure. Because the increase in expo-sure of empagliflozin in patients with T2DM withvarious degrees of renal impairment was o2-fold inthis study and empagliflozin 50 mg (double the dose

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investigated in this study) was found to be welltolerated in a 12-week empagliflozin dose-finding studyin Japanese patients,18 no dose adjustment ofempagliflozin is required in Japanese patients withT2DM and mild, moderate, or severe renalimpairment from a pharmacokinetic perspective.

A single dose of empagliflozin 25 mg was used,representing the highest dose investigated in Phase IIItrials. The pharmacokinetic and pharmacodynamicresults of empagliflozin 25 mg therapy can be extrapo-lated to the 10 mg dose because empagliflozin exhibitslinear pharmacokinetic properties14 and effects on UGEappear to plateau above a dose of 10 mg.11

As expected from the mechanism of action ofSGLT2 inhibitors, empagliflozin-induced UGE de-creased with increasing severity of renal impairment.Although empagliflozin had a limited effect on UGE inJapanese patients with T2DM with severe renalimpairment, indicating limited glucose-lowering effi-cacy in these patients, in patients with mild ormoderate renal impairment increases in UGE wereobserved that would be expected to translate intoclinically meaningful reductions in glycosylated hemo-globin. Overall, similar results were reported in adedicated study of non-Japanese patients with variousdegrees of renal impairment,16 suggesting that thereare no marked ethnic differences in the effect of renalimpairment on the pharmacokinetic or pharmaco-dynamic properties of empagliflozin.

In this study, a single dose of empagliflozin 25 mgwas well tolerated. No clinically relevant changes invital signs or clinical laboratory values were noted inany patient. This is consistent with a study of non-Japanese patients with renal impairment in whomempagliflozin was well tolerated with no increase inAEs associated with renal impairment.16

CONCLUSIONSThe pharmacokinetic results suggest that no doseadjustment of empagliflozin is required in Japanesepatients with T2DM and mild, moderate, or severerenal impairment. A single dose of empagliflozin 25mg was well tolerated in Japanese patients withT2DM and renal impairment.

ACKNOWLEDGMENTSThis study was funded by Boehringer Ingelheim.Medical writing assistance, supported financially byBoehringer Ingelheim, was provided by Clare Ryles

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and Stephanie Lockett of Fleishman-Hillard Group Ltdduring the preparation of the manuscript. The authorswere fully responsible for all content and editorialdecisions, were involved at all stages of manuscriptdevelopment, and have approved the final version.

CONFLICTS OF INTERESTThis study was funded by Boehringer Ingelheim.Akiko Sarashina, Tomohiro Sasaki, Yuko Tanaka,Kazuki Koiwai, Wataru Sakamoto, Hans J. Woerle,Afshin Salsali, Uli C. Broedl and Sreeraj Macha areemployees of Boehringer Ingelheim. Kojiro Ueki hasbeen a speaker for Novo Nordisk, Takeda, MSD,Sanofi-Aventis, Eli Lilly, Novartis, Astellas, Daiichi-Sankyo and Boehringer Ingelheim and has receivedgrants from Sanofi, Takeda, Novo Nordisk and MSD.The authors meet criteria for authorship as recom-mended by the International Committee of MedicalJournal Editors (ICMJE). Akiko Sarashina, KojiroUeki, Tomohiro Sasaki, Yuko Tanaka, Kazuki Koi-wai, Wataru Sakamoto and Sreeraj Macha madesubstantial contributions to the conception and de-sign, Yuko Tanaka and Kazuki Koiwai were involvedin the acquisition of data, and Akiko Sarashina,Tomohiro Sasaki, Yuko Tanaka, Kazuki Koiwai,Wataru Sakamoto, Afshin Salsali, Sreeraj Machaand Uli C. Broedl were involved in the analysis andinterpretation of data. All authors were involved withdrafting the article or revising it critically for impor-tant intellectual content and all authors have ap-proved the final version to be published.

REFERENCES1. International Diabetes Federation. IDF Diabetes Atlas, 6th

edn. Brussels, Belgium: 2013 update. http://www.idf.org/diabetesatlas/download-book. Accessed February 18, 2014.

2. Neville SE, Boye KS, Montgomery WS, et al. Diabetes inJapan: a review of disease burden and approaches totreatment. Diabetes Metab Res Rev. 2009;25:705–716.

3. Yokoyama H, Sone H, Oishi M, et al. Prevalence ofalbuminuria and renal insufficiency and associated clinicalfactors in type 2 diabetes: the Japan Diabetes ClinicalData Management study (JDDM15). Nephrol Dial Trans-plant. 2009;24:1212–1219.

4. Meguro S, Tomita M, Kabeya Y, et al. Factors associatedwith the decline of kidney function differ among eGFRstrata in subjects with type 2 diabetes mellitus. Int J

Endocrinol. 2012;2012:687867.5. [KDIGO] Kidney Disease: Improving Global Outcomes

(KDIGO) CKD Work Group. KDIGO 2012 Clinical

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Practice Guideline for the Evaluation and Managementof Chronic Kidney Disease. Kidney Int Suppl. 2013;3:1–150.

6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management ofhyperglycemia in type 2 diabetes: a patient-centered ap-proach: position statement of the American Diabetes Asso-ciation (ADA) and the European Association for the Study ofDiabetes (EASD). Diabetes Care. 2012;35:1364–1379.

7. Nakai S, Iseki K, Itami N, et al. Overview of regular dialysistreatment in Japan (as of 31 December 2010). Ther ApherDial. 2012;16:11–53.

8. Food and Drug Administration. Guidance for Industry:Pharmacokinetics in patients with impaired renal function— study design, data analysis, and impact on dosing andlabelling. 2010. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM204959.pdf. Accessed April 25, 2013.

9. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin,a novel selective sodium glucose cotransporter-2 (SGLT-2)inhibitor: characterisation and comparison with otherSGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90.

10. Gerich JE. Role of the kidney in normal glucose homeo-stasis and in the hyperglycaemia of diabetes mellitus:therapeutic implications. Diabet Med. 2010;27:136–142.

11. Heise T, Seewaldt-Becker E, Macha S, et al. Safety,tolerability, pharmacokinetics and pharmacodynamicsfollowing 4 weeks’ treatment with empagliflozin oncedaily in patients with type 2 diabetes. Diabetes Obes Metab.2013;15:613–621.

12. Heise T, Seman L, Macha S, et al. Safety, tolerability,pharmacokinetics, and pharmacodynamics of multiplerising doses of empagliflozin in patients with type 2diabetes mellitus. Diab Ther. 2013;4:331–345.

13. Kanada S, Koiwai K, Taniguchi A, et al. pharmacody-namics, safety and tolerability of 4 weeks’ treatment withempagliflozin in Japanese patients with type 2 diabetesmellitus. J Diabetes Investig. 2013;4:613–617.

14. Seman L, Macha S, Nehmiz G, et al. Empagliflozin (BI10773), a potent and selective SGLT-2 inhibitor, inducesdose-dependent glucosuria in healthy subjects. Clinical

Pharm Drug Dev. 2013;2:152–161.15. Sarashina A, Koiwai K, Seman LJ, et al. Safety, tolerability,

pharmacokinetics and pharmacodynamics of single dosesof empagliflozin, a sodium glucose cotransporter-2(SGLT-2) inhibitor, in healthy Japanese subjects. Drug

Metab Pharmacokinet. 2013;28:213–219.16. Macha S, Mattheus M, Halabi A, et al. pharmacodynam-

ics and safety of empagliflozin, a sodium glucose cotrans-porter 2 (SGLT2) inhibitor, in subjects with renalimpairment. Diabetes Obes Metab. 2014;16:215–222.

17. Matsuo S, Imai E, Horio M, et al. Collaborators devel-oping the Japanese equation for estimated GFR: revisedequations for estimated GFR from serum creatinine inJapan. Am J Kidney Dis. 2009;53:982–992.

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A. Sarashina et al.

18. Kadowaki T, Haneda M, InagakiN, et al. Empagliflozin monother-apy for 12 weeks improves glyce-mic control in Japanese patientswith type 2 diabetes (T2DM).Diabetes. 2013;62(suppl 1):A297–A298 [1144-P].

November 2014

Address correspondence to: Akiko Sarashina, Nippon Boehringer Ingel-heim Co Ltd, Medical Development Division, Clinical PK/PD Depart-ment, Hyogo, Japan. E-mail: akiko.sarashina@boehringer-ingelheim.com

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