Clinical Therapeutics/Volume 37, Number 4, 2015
Assessing Pharmacokinetic Interactions Between the Sodium Glucose Cotransporter 2 Inhibitor Empagliflozin and Hydrochlorothiazide or Torasemide in Patients With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Crossover Study Tim Heise, MD1; Michaela Mattheus2; Hans J. Woerle, MD2; Uli C. Broedl, MD2; and Sreeraj Macha, PhD3 1
Profil Institut fu¨r Stoffwechselforschung GmbH, Neuss, Germany; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; and 3Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA
ABSTRACT Purpose: Empagliflozin is a potent, selective sodium glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus. Thiazide or loop diuretics are commonly prescribed in patients with type 2 diabetes mellitus. This study investigated potential pharmacokinetic drugdrug interactions between empagliflozin and hydrochlorothiazide (HCTZ) or torasemide (TOR). Methods: This was an open-label, crossover study. Patients with type 2 diabetes mellitus were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days followed by TOR 5 mg once daily plus empagliflozin once daily for 5 days in 1 of 4 sequences, with at least a 7-day washout period between treatments. Pharmacokinetic parameters of empagliflozin, HCTZ, and TOR were assessed and standard bioequivalence criteria (80%125%) were applied. Tolerability assessments included the frequency of adverse events and an investigator assessment of global tolerability. Findings: Mean (SD) age of the 22 patients treated was 54.0 (8.1) years and body mass index was 27.1 (3.7) kg/m2. Coadministration of empagliflozin with HCTZ or TOR had no effect on exposure to empagliflozin, HCTZ, or TOR. Geometric mean ratios (90% CIs) for empagliflozin AUC over a uniform dosing interval and Cmax at steady state were 107.1% (90% CI, 97.1118.1) and 102.8% (90% CI, 88.6119.3), respectively, when coadministered with HCTZ versus administration alone,
April 2015
and 107.8% (90% CI, 100.1116.1) and 107.5% (90% CI, 97.9118.0), respectively, when coadministered with TOR versus administration alone. For HCTZ, the geometric mean ratios for AUC over a uniform dosing interval and Cmax at steady state were 96.3% (90% CI, 89.1104.0) and 101.8% (90% CI, 88.6116.9), respectively, and for TOR were 101.4% (90% CI, 99.1103.9) and 104.4% (90% CI, 93.8116.3), respectively, for combined treatment versus administration alone. The pharmacokinetic profiles of empagliflozin, HCTZ, and TOR were similar after administration alone and in combination. Global tolerability was good for all patients after each treatment, and no severe or serious adverse events were reported. Implications: No pharmacokinetic drugdrug interaction was observed between empagliflozin and HCTZ or TOR. ClinicalTrials.gov identifier: NCT01276288. (Clin Ther. 2015;37:793–803) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: drugdrug interaction, empagliflozin, hydrochlorothiazide, pharmacokinetic properties, torasemide.
INTRODUCTION Empagliflozin is a potent and selective sodium glucose cotransporter 2 inhibitor1 approved for the treatment of type 2 diabetes mellitus (T2DM). By blocking Accepted for publication December 21, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.12.018 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
793
Clinical Therapeutics sodium glucose cotransporter 2, which is expressed on the luminal surface of epithelial cells in the proximal renal tubule, empagliflozin reduces renal glucose reabsorption, leading to increased urinary glucose excretion and a reduction in hyperglycemia in patients with T2DM.2 Approximately 11% to 19% of the administered empagliflozin dose is excreted unchanged in urine after oral administration.3 After multiple oral doses of empagliflozin up to 100 mg once daily for 4 weeks in patients with T2DM, empagliflozin was rapidly absorbed (reaching peak levels after 1.5 hours) and had a mean terminal elimination half-life between 13 and 17 hours.2 In Phase III studies, patients receiving empagliflozin had improved glycemic control and reduced weight and blood pressure, and empagliflozin was well tolerated when used as monotherapy or as add on to other antidiabetes therapies.4–8 Hypertension affects approximately two thirds of patients with diabetes9 and diuretics are the most commonly used antihypertensive drug class.10,11 Diuretics are also used in the treatment of renal insufficiency and edematous disorders, such as chronic heart failure,12 which are common complications of diabetes. Thiazide and loop diuretic agents are used to inhibit sodium reabsorption (in addition to other electrolytes) in the renal tubules.12 As antidiabetes medications are likely to be used in combination with diuretics in patients with T2DM, and as both diuretics and empagliflozin may modulate sodium and water homeostasis, this study was undertaken to investigate potential pharmacokinetic interactions between empagliflozin and the thiazide diuretic hydrochlorothiazide (HCTZ) or the loop diuretic torasemide (TOR) in patients with T2DM.
PATIENTS AND METHODS This was a randomized, open-label, crossover study undertaken at a single center in Germany. The study protocol was approved by the appropriate competent authority (Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany) and the local independent ethics committee (Ärtzekammer Nordrhein, Düsseldorf, Germany). The study was conducted in compliance with the protocol, the principles of the Declaration of Helsinki, International Conference on Harmonization Tripartite Guideline for Good Clinical Practice, and applicable regulatory requirements. All
794
patients provided written, informed consent before enrollment into the study.
Patients Screening took place 18 to 35 days before the first administration of study drug. Patients with T2DM aged 20 to 65 years with a body mass index of 20 to 35 kg/m2 were eligible for inclusion if they had been treated with metformin alone for at least 12 weeks before screening and had normal renal function (estimated glomerular filtration rate Z60 mL/min/ 1.73 m2, according to the Modification of Diet in Renal Disease equation). Major exclusion criteria were treatment with antidiabetic drugs other than metformin within the last 12 weeks; repeated measurement of systolic blood pressure o90 or Z160 mm Hg or diastolic blood pressure o60 or Z100 mm Hg; history of relevant orthostatic reaction; alanine aminotransferase, aspartate aminotransferase, or gamma-glutamyl transferase Z2 times the upper limit of normal; acute, chronic, or recurrent urinary or genital tract infection; microalbuminuria Z20 mg/L; clinical conditions associated with micturition difficulties; gout; clinical signs of hypovolemia; and clinically relevant laboratory abnormalities, including glycosylated hemoglobin r6.5% or Z10% and fasting plasma glucose Z240 mg/dL.
Study Design and Treatments Eligible patients were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days, followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days, followed by TOR 5 mg once daily plus empagliflozin 25 mg once daily for 5 days, in 1 of 4 randomized sequences (Figure 1) in a 1:1:1:1 ratio. Study drugs were administered with 240 mL water after an overnight fast of at least 10 hours; fluid intake was not permitted from 1 hour before until 1 hour after study drug administration and was restricted to approximately 45 mL/kg body weight/d (including water content of food). Treatment with empagliflozin alone was separated from treatment with a diuretic plus empagliflozin by a washout period of at least 7 days. Metformin was continued during the study, except on the last 2 days of treatment with empagliflozin alone (days 4 and 5), diuretic alone (days 3 and 4), and empagliflozin plus a diuretic (days
Volume 37 Number 4
T. Heise et al. Day4 Day5
Day1
Day9
Day1
Day9
Empagliflozin 25 mg qd
Empagliflozin 25 mg qd
HCTZ 25 mg qd
Day4 Day5
HCTZ 25 mg qd + empagliflozin 25 mg qd
≥7-day washout
HCTZ 25 mg qd
HCTZ 25 mg qd + empagliflozin 25 mg qd
Randomization
Empagliflozin 25 mg qd
TOR 5 mg qd
Day1
TOR 5 mg qd + empagliflozin 25 mg qd
Day4 Day5
Empagliflozin 25 mg qd
≥7-day washout
Day9
Day1
TOR 5 mg qd
TOR 5 mg qd + empagliflozin 25 mg qd
Day4 Day5
Day9
Figure 1. Study design and disposition of patients. HCTZ ¼ hydrochlorothiazide; TOR ¼ torasemide; qd ¼ once daily.
8 and 9). Patients were inpatients at the study site from day 3 to day 6 when receiving empagliflozin alone, and day 3 to day 10 when receiving a diuretic plus empagliflozin; all study drugs were administered from day 1. Food, fluid, and salt intake were standardized during confinement to the study site.
Sample Collection and Analysis Blood samples for pharmacokinetic analyses were taken from the forearm vein in K3-EDTA tubes at the following time points on day 5 for empagliflozin alone, on day 4 of diuretic alone, and day 9 for diuretic plus empagliflozin: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours post dose. Samples were stored on ice for r60 minutes then centrifuged for approximately 10 minutes at 2500 g and 41C. All urine voided on day 5 (empagliflozin alone), on day 4 (diuretic alone), and on day 9 (diuretic plus empagliflozin) was collected (sampling periods: 04, 48, 812, and 1224 hours). Plasma samples and urine samples were stored at 201C or below until shipment on dry ice for analysis. Empagliflozin and its internal standard, [13C6] empagliflozin, were extracted from plasma and urine samples using supported liquid extraction. After evaporation under nitrogen, the residue was reconstituted
April 2015
before analysis. HCTZ and its internal standard, HCTZ-13C,D2, were extracted from plasma by protein precipitation with acetonitrile and the supernatant was transferred, washed with hexane, and transferred again before analysis. HCTZ and its internal standard were extracted from urine by acidifying the sample before analysis. TOR and its active metabolites, TORM1 and TOR-M3, and their internal standards, TORd7, TOR-M1-d7, and TOR-M3-d7, respectively, were extracted from plasma by acidification followed by solid-phase extraction and evaporation under nitrogen; the residue was reconstituted before analysis. TOR, TOR-M1, and TOR-M3 and their internal standards were extracted from urine by protein precipitation with acetonitrile. A portion of the supernatant was diluted with water before analysis. Concentrations of empagliflozin, HCTZ, TOR, TOR-M1, and TOR-M3 in plasma and urine were determined using validated methods of LC-MS/MS. Calibration curves were created using weighted (1/2) 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. Mean r2s for calibration curves were
795
Clinical Therapeutics 0.996 to 1.000. For all methods, analysis of qualitycontrol samples found 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% criteria). For quality-control samples of empagliflozin in urine, inter-run precision and accuracy ranged from 3.7% to 7.5% and 0% to 7.2%, respectively. The lower limit of quantitation for empagliflozin in plasma (0.15-mL sample) was 1.11 nmol/L, with linearity up to 1110 nmol/L and in urine (0.05-mL sample) was 4.44 nmol/L, with linearity up to 4440 nmol/L. For HCTZ in plasma, inter-run precision and accuracy ranged from 1.7% to 5.5% and 7.4% to 0.5%, respectively, and for HCTZ in urine ranged from 1.5% to 3.4% and 2.6% to 2.0%, respectively. The lower limit of quantitation for HCTZ in plasma (0.15-mL sample) was 1 ng/mL, with linearity up to 500 ng/mL, and in urine (0.05-mL sample) was 100 ng/mL, with linearity up to 10,000 ng/mL. For TOR in plasma, inter-run precision and accuracy ranged from 1.8% to 8.7% and 10.1% to 2.4%, respectively, and for TOR in urine ranged from 3.6% to 7.7% and 4.5% to 2.6%, respectively. The lower limit of quantitation for TOR in plasma was 1 ng/mL, with linearity up to 1000 mg/mL, and in urine was 10 ng/mL, with linearity up to 10,000 ng/mL (0.05-mL samples). For TOR-M1 in plasma, inter-run precision and accuracy ranged from 1.8% to 8.6% and 12.8% to 2.0%, respectively, and for TOR-M1 in urine ranged from 3.8% to 11.8% and 4.6% to 5.0%, respectively. For TOR-M3 in plasma, inter-run precision and accuracy ranged from 2.9% to 6.2% and 5.3% to 2.5%, respectively, and for TOR-M3 in urine ranged from 3.4% to 11.7% and 4.3% to 2.5%, respectively. The lower limit of quantitation for TOR-M1 and TOR-M3 in plasma was 0.5 ng/mL, with linearity up to 500 ng/mL, and in urine was 1 ng/mL, with linearity up to 1000 ng/mL (0.05-mL samples).
Pharmacokinetic Assessments Pharmacokinetic parameters assessed included the AUC at steady state over a uniform dosing period τ (AUCτ,ss), Cmax,ss, Tmax,ss, t1/2,ss, renal clearance at steady state, the fraction of the dose excreted unchanged in urine over 24 hours at steady state, mean residence time in the body after oral administration at steady state, apparent clearance in plasma after
796
extravascular administration at steady state, and apparent volume of distribution during the terminal phase after an extravascular dose at steady state for empagliflozin, HCTZ, TOR, and the active metabolites of TOR, TOR-M1, and TOR-M3. Pharmacokinetic parameters were calculated using WinNonlinTM software, version 5.2 (Pharsight Corporation, Mountain View, California). Cmax and Tmax values were directly determined from the plasma concentration time profiles of each subject. The terminal half-life was calculated as the quotient of ln (2) and the terminal rate constant (λz). λz was estimated from a regression of ln(C) versus time over the terminal log-linear drug disposition portion of the concentration-time profiles. The fraction of the dose excreted unchanged in urine over 24 hours at steady state was determined by the quotient of the sum of drug excreted over all dosing intervals and the dose administered. Renal clearance was determined as the quotient of fraction of dose excreted unchanged in urine dose / AUC.
Pharmacodynamic Assessments Detailed pharmacodynamics assessments were conducted as part of this study; these results will be reported elsewhere.
Safety Assessments Safety assessments were conducted throughout the study. Data on adverse events (AEs), coded using the Medical Dictionary for Regulatory Activities, version 15.0, were collected from administration of the first dose of study drug. Safety assessments included vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate), clinical laboratory evaluations, a 12lead resting ECG, and physical examination. Blood pressure was measured after the patients had rested for Z10 minutes in the supine position using a Boso Medicus Control (Bosch & Sohn GmbH & Co. KG, Jungingen, Germany). The investigator assessed global tolerability based on AEs and laboratory evaluations at the end of each treatment period.
Statistical Analyses Statistical analyses were performed with SAS software, version 9.2 (SAS Institute Inc., Cary, North Carolina). Pharmacokinetic assessments were performed in all subjects who took at least one dose of study drug and had at least one observation for AUCτ,ss
Volume 37 Number 4
T. Heise et al. or Cmax,ss for any analyte (without any protocol violations relevant to the pharmacokinetic evaluation). Safety analyses were performed based on all patients who took at least one dose of study drug. The relative bioavailability of HCTZ, TOR, or empagliflozin coadministered (test) compared with administration alone (reference) were assessed using an ANCOVA model based on log transformed (ln) AUCτ,ss or Cmax,ss values. The ANCOVA model for comparison of HCTZ and TOR treatment groups included treatment as fixed effect and subject as random effect, and the model for comparison of empagliflozin treatment groups included treatment, sequence, and period as fixed effects and subject within sequence as a random effect. The difference between the expected means for log(test) log(reference) was estimated by the difference in the corresponding least square means (point estimate) and 2-sided 90% CIs based on the t distribution were calculated. These values were back transformed to the original scale to give the geometric mean ratio and 2-sided 90% CIs for response under test versus reference conditions. Standard bioequivalence boundaries (80%125%) were applied for the 90% CIs of the geometric mean ratio.
RESULTS Study Population Of 38 patients with T2DM screened, 23 patients entered the study. Of those, 13 patients were randomized to receive empagliflozin and HCTZ, and 10 patients were randomized to receive empagliflozin and TOR. One patient who was randomized to receive empagliflozin and HCTZ discontinued before first intake of study drug. Of the 22 treated patients, 15 (68%) were male, mean (SD) age was 54.0 (8.1) years, and body mass index was 27.1 (3.7) kg/m2. Two patients discontinued due to AEs, one who received empagliflozin alone in the first treatment period but did not receive HCTZ or empagliflozin during the second treatment period, and one who received HCTZ in the first treatment period, but did not receive empagliflozin in either treatment period. Therefore, 20 patients completed the study.
Pharmacokinetics of Empagliflozin Steady-state levels of empagliflozin 25 mg had been achieved by day 5. Empagliflozin 25 mg was rapidly absorbed (median Tmax 1.5 hours) and plasma levels
April 2015
declined in a biphasic fashion, displaying a rapid distribution phase and a slower elimination phase (Table I and Figure 2). Plasma-concentration time curves and pharmacokinetic properties for empagliflozin 25 mg were similar when empagliflozin was administered alone and coadministered with HCTZ or TOR (Table I and Figure 2). Coadministration with HCTZ or TOR had no effect on steady-state pharmacokinetic properties of empagliflozin based on the standard bioequivalence boundaries (80%125%; Table II).
Pharmacokinetics of Hydrochlorothiazide Steady-state levels of HCTZ 25 mg had been achieved by day 4. HCTZ was rapidly absorbed (median Tmax 1.5 hours) and plasma levels declined in a biphasic fashion (Table III and Figure 3). Plasmaconcentration time curves and pharmacokinetic parameters for HCTZ 25 mg were similar when HCTZ was administered alone and coadministered with empagliflozin (Figure 3 and Table III). Coadministration with empagliflozin had no effect on steady-state pharmacokinetic properties of HCTZ when standard bioequivalence boundaries were applied (Table II).
Pharmacokinetics of Torasemide Steady-state levels of TOR 5 mg had been achieved by day 4. TOR was rapidly absorbed (median Tmax 0.5 hours) and plasma levels declined rapidly in a biphasic fashion. Plasma-concentration time curves and pharmacokinetic parameters for TOR 5 mg, and its active metabolites TOR-M1 and TOR-M3, were similar when TOR was administered alone and coadministered with empagliflozin (Figure 4 and Table IV). Coadministration with empagliflozin had no effect on steady-state exposure to TOR (Table II). Coadministration with empagliflozin also had no effect on steady-state exposure to TOR-M1 and TOR-M3 (Table II).
Tolerability No serious or severe AEs were reported during the trial. Thirst was the most frequently reported drugrelated AE, and was only reported during combination therapy (2 patients receiving empagliflozin plus HCTZ, and 6 receiving empagliflozin plus TOR). Two AEs led to premature trial termination: 1 patient experienced atrial tachycardia after 4 doses of HCTZ and 1 patient showed increased alanine aminotransferase values (Z2 times the upper limit of normal) after treatment with
797
Clinical Therapeutics
Table I. Pharmacokinetic properties of empagliflozin 25 mg once daily administered alone versus in combination with hydrochlorothiazide 25 mg once daily or torasemide 5 mg once daily. Empagliflozin 25 mg þ HCTZ 25 mg (n ¼ 10)†
Empagliflozin 25 mg (n ¼ 21)*
Parameters AUCτ,ss, nmol h/L, mean, %CV Cmax,ss, nmol/L, mean, %CV Tmax,ss, h, median (range) t½,ss, h, mean, %CV fe024,ss, %, mean, %CV CLR,ss, mL/min, mean, %CV MRTpo,ss, h, mean, %CV CL/Fss, mL/min, mean, %CV Vz/Fss, L, mean, %CV
5090 961 1.5 15.3 19.4 36.7 12.5 189 248
(21.8) (23.1) (1.02.0) (47.4) (21.1) (31.4) (37.0) (20.3) (50.3)
5720 1070 1.5 14.8 17.7 30.2 12.3 171 221
Empagliflozin 25 mg þ TOR 5 mg (n ¼ 10)
(24.1) (29.0) (1.01.5) (18.1) (30.0) (36.0) (12.2) (25.4) (36.7)
5340 969 1.0 16.1 18.0 32.5 12.5 179 247
(18.9) (21.0) (1.01.5) (14.4) (14.2) (31.4) (17.2) (19.3) (20.6)
AUCτ ¼ area under the concentration-time curve over a uniform dosing period τ; CL/F ¼ apparent clearance in plasma after extravascular administration; CLR ¼ renal clearance; Cmax ¼ maximum plasma concentration; fe024 ¼ fraction of dose excreted unchanged in urine over 24 hours; HCTZ ¼ hydrochlorothiazide; MRTpo ¼ mean residence time in the body after oral administration; ss ¼ steady state; Tmax ¼ time to Cmax; t½ ¼ terminal half-life; TOR ¼ torasemide; Vz/F ¼ apparent volume of distribution during the terminal phase after an extravascular dose. * One patient randomized to receive empagliflozin alone/HCTZ plus empagliflozin received empagliflozin alone, but did not receive empagliflozin or HCTZ in the second treatment period. † One patient randomized to receive HCTZ plus empagliflozin/empagliflozin alone received HCTZ but did not receive empagliflozin in either treatment period.
empagliflozin during the run-in phase to the start of the second treatment period. Overall, with the exception of atrial tachycardia and the increase in alanine aminotransferase, there
Empagliflozin plasma concentration (nmol/L)
10,000
were no additional clinically relevant changes in safety laboratory parameters and ECG records. Systolic and diastolic blood pressure generally tended to decrease and pulse rate slightly increased. Global tolerability,
Empagliflozin 25 mg alone (n = 21) Empagliflozin 25 mg with HCTZ 25 mg (n = 10) Empagliflozin 25 mg with TOR 5 mg (n = 10)
1000
100
10 0
4
8
12 Time (hours)
16
20
24
Figure 2. Arithmetic mean (SD) plasma concentration time curve of empagliflozin after administration of empagliflozin 25 mg once daily alone and with hydrochlorothiazide (HCTZ) 25 mg once daily or torasemide (TOR) 5 mg once daily.
798
Volume 37 Number 4
T. Heise et al.
Table II. Relative bioavailability of empagliflozin 25 mg once daily administered in combination with hydrochlorothiazide 25 mg once daily or torasemide 5 mg once daily, hydrochlorothiazide 25 mg once daily administered in combination with empagliflozin 25 mg once daily, and torasemide 5 mg once daily administered in combination with empagliflozin 25 mg once daily versus administration alone. 90% CI for GMR Parameter AUCτ,ss Cmax,ss AUCτ,ss Cmax,ss AUCτ,ss Cmax,ss TOR AUCτ,ss Cmax,ss TOR-M1 AUCτ,ss Cmax,ss TOR-M3 AUCτ,ss Cmax,ss
Test
Reference
GMR, %
Lower Limit, %
Upper Limit, %
Empagliflozin (n ¼ 11) Empagliflozin (n ¼ 11) Empagliflozin (n ¼ 10) Empagliflozin (n ¼ 10) HCTZ (n ¼ 11) HCTZ (n ¼ 11)
107.08 102.78 107.83 107.50 96.27 101.77
97.11 88.55 100.14 97.90 89.08 88.63
118.07 119.29 116.11 118.04 104.05 116.85
TOR þ empagliflozin (n ¼ 10) TOR þ empagliflozin (n ¼ 10)
TOR (n ¼ 10) TOR (n ¼ 10)
101.44 104.43
99.06 93.81
103.88 116.25
TOR þ empagliflozin (n ¼ 10) TOR þ empagliflozin (n ¼ 10)
TOR (n ¼ 10) TOR (n ¼ 10)
104.42 102.67
100.39 94.13
108.62 111.97
TOR þ empagliflozin (n ¼ 10) TOR þ empagliflozin (n ¼ 10)
TOR (n ¼ 10) TOR (n ¼ 10)
103.19 102.42
95.93 97.65
111.01 107.42
Empagliflozin þ HCTZ Empagliflozin þ HCTZ Empagliflozin þ TOR Empagliflozin þ TOR HCTZ þ empagliflozin HCTZ þ empagliflozin
(n (n (n (n (n (n
¼ ¼ ¼ ¼ ¼ ¼
10) 10) 10) 10) 10) 10)
AUCτ ¼ area under the concentration-time curve over a uniform dosing period τ; CI ¼ confidence interval; Cmax ¼ maximum plasma concentration; GMR ¼ geometric mean ratio; HCTZ ¼ hydrochlorothiazide; ss ¼ steady state; TOR ¼ torasemide.
Table III. Pharmacokinetic properties of hydrochlorothiazide 25 mg once daily administered alone versus in combination with empagliflozin 25 mg once daily. Parameter AUCτ,ss, nmol h/L, %CV Cmax,ss, nmol/L, %CV Tmax,ss, h, median (range) t½,ss, h, %CV fe0–24,ss, %, %CV CLR,ss, mL/min, %CV MRTpo,ss, h, %CV CL/Fss, mL/min, %CV Vz/Fss, L, %CV
HCTZ 25 mg (n ¼ 11)* 1050 211 1.5 10.6 72.1 291 10.1 408 369
(18.3) (26.2) (1.03.0) (27.0) (20.5)‡ (24.7)‡ (21.1) (17.2) (27.8)
HCTZ 25 mg þ Empagliflozin 25 mg (n ¼ 10)† 1020 213 1.8 13.5 67.7 289 11.3 422 494
(18.1) (28.7) (1.02.0) (26.7) (27.2) (34.4) (21.0) (18.9) (29.8)
AUCτ ¼ area under the concentration-time curve over a uniform dosing period τ; CL/F ¼ apparent clearance in plasma after extravascular administration; CLR ¼ renal clearance; Cmax = maximum plasma concentration; fe024 ¼ fraction of dose excreted unchanged in urine over 24 hours; HCTZ ¼ hydrochlorothiazide; MRTpo ¼ mean residence time in the body after oral administration; ss ¼ steady state; Tmax ¼ time to Cmax; t½ ¼ terminal half-life; Vz/F ¼ apparent volume of distribution during the terminal phase after an extravascular dose. * One patient randomized to receive HCTZ plus empagliflozin/empagliflozin alone received HCTZ but did not receive empagliflozin in either treatment period. † One patient randomized to receive empagliflozin alone/HCTZ plus empagliflozin received empagliflozin alone, but did not receive HCTZ or empagliflozin in the second treatment period. ‡ n ¼ 10.
April 2015
799
Clinical Therapeutics
Hydrochlorothiazide plasma concentration (ng/mL)
1000
HCTZ 25 mg alone (n = 11) HCTZ 25 mg with empagliflozin 25 mg (n = 10)
100
10 0
8
4
12 Time (hours)
16
20
24
Figure 3. Arithmetic mean (SD) plasma concentrations of hydrochlorothiazide (HCTZ) after administration of HCTZ 25 mg once daily alone and with empagliflozin 25 mg once daily.
as assessed by the investigator, was “good” for all patients after each treatment period.
DISCUSSION We undertook this open-label, crossover study to investigate any relevant interactions between empagliflozin and HCTZ or TOR in patients with T2DM. Empagliflozin is not extensively metabolized, with unchanged
TOR with TOR 5 mg alone (n = 10) TOR with TOR 5 mg plus empagliflozin 25 mg (n = 10) TOR-M1 with TOR 5 mg alone (n = 10) TOR-M1 with TOR 5 mg plus empagliflozin 25 mg (n = 10) TOR-M3 with TOR 5 mg alone (n = 10) TOR-M3 with TOR 5 mg plus empagliflozin 25 mg (n = 10)
1000 Plasma concentration (ng/mL)
empagliflozin the most abundant drug-related component in the plasma, and approximately 11% to 19% of the administered dose is excreted unchanged in urine (data not published). No major metabolites of empagliflozin were detected in human plasma and glucuronidation was the major metabolic pathway (data not published). HCTZ is not metabolized in humans, but is excreted almost entirely unchanged in urine.12 In
100
10
1
0.1 0
4
8
12 Time (hours)
16
20
24
Figure 4. Arithmetic mean (SD) plasma concentrations of torasemide (TOR) and its active metabolites TORM1 and TOR-M3 after administration of TOR 5 mg once daily alone and with empagliflozin 25 mg once daily.
800
Volume 37 Number 4
T. Heise et al.
Table IV. Pharmacokinetic properties of torasemide and its active metabolites torasemide-M1 and torasemide-M3 after torasemide 5 mg administered alone versus in combination with empagliflozin 25 mg once daily. Parameter TOR AUCτ,ss, nmol h/L, %CV Cmax,ss, nmol/L, %CV Tmax,ss, h, median (range) t½,ss, h, %CV fe024,ss, %, %CV CLR,ss, mL/min, %CV MRTpo,ss, h, %CV CL/Fss, mL/min, %CV Vz/Fss, L, %CV TOR-M1 AUCτ,ss, nmol h/L, %CV Cmax,ss, nmol/L, %CV Tmax,ss, h, median (range) t½,ss, h, %CV fe024,ss, %, %CV CLR,ss, mL/min, %CV MRTpo,ss, h, %CV CL/Fss, mL/min, %CV Vz/Fss, L, %CV TOR-M3 AUCτ,ss, nmol h/L, %CV Cmax,ss, nmol/L, %CV Tmax, h, median (range) t½, h, %CV fe024,ss, %, %CV CLR,ss, mL/min, %CV MRTpo,ss, h, %CV CL/Fss, mL/min, %CV Vz/Fss, L, %CV
TOR 5 mg (n ¼ 10)
TOR 5 mg þ Empagliflozin 25 mg (n ¼ 10)
1340 721 0.5 4.8 22.4 14.2 3.2 63.4 26.1
(14.4) (18.4) (0.51.5) (17.1) (25.2) (25.7) (18.2) (13.4) (20.0)
1360 747 0.5 4.6 21.8 14.0 3.1 62.7 24.7
(16.2) (12.1) (0.51.0) (13.9) (32.0) (42.4) (15.8) (15.7) (19.1)
75.7 43.7 0.5 2.6 18.8 211 2.4 1130 244
(16.4) (25.0) (0.51.5) (24.5) (20.5) (24.6) (25.2) (15.2) (20.4)
79.2 44.4 0.5 2.5 17.0 185 2.3 1080 230
(17.4) (18.0) (0.51.0) (28.4) (32.3) (37.3) (19.3) (17.6) (28.4)
41.5 8.6 1.5 3.7 3.09 65.1 5.3 2110 653
(23.1) (12.7) (1.02.0) (21.8) (9.98) (27.3) (22.2) (23.9) (20.3)
42.4 8.9 1.5 3.8 2.89 58.9 5.3 2020 652
(17.9) (17.1) (1.02.0) (25.3) (17.5) (26.6) (21.6) (18.0) (30.9)
AUCτ ¼ area under the concentration-time curve over a uniform dosing period τ; CLR ¼ renal clearance; CL/F ¼ apparent clearance in plasma after extravascular administration; Cmax ¼ maximum plasma concentration; fe024 ¼ fraction of dose excreted unchanged in urine over 24 hours; MRTpo ¼ mean residence time in the body after oral administration; ss ¼ steady state; Tmax ¼ time to Cmax; t½ ¼ terminal half-life; TOR ¼ torasemide; Vz/F ¼ apparent volume of distribution during the terminal phase after an extravascular dose.
contrast, only 20% to 21% of the dose of TOR is excreted unchanged in the urine.13,14 TOR undergoes extensive hepatic metabolism; 2 minor metabolites have pharmacologic activity, TOR-M1 and TOR-M3.12 Approximately 10% to 12% of the dose is excreted in
April 2015
the urine as TOR-M1 and approximately 2% of the dose is excreted in the urine as TOR-M3.13,14 Coadministration of empagliflozin with HCTZ or TOR had no effect on the pharmacokinetic properties of empagliflozin, HCTZ, TOR, TOR-M1, or TOR-M3.
801
Clinical Therapeutics The geometric mean ratios and corresponding 90% CIs for AUCτ,ss and Cmax,ss for empagliflozin, HCTZ, TOR, TOR-M1, and TOR-M3 were all contained within the standard acceptance limits for bioequivalence of 80% to 125%. In addition, the renal clearance at steady state and fraction of the dose excreted unchanged in urine over 24 hours at steady state of empagliflozin, HCTZ, and TOR were similar when administered alone or when empagliflozin was coadministered with HCTZ or TOR (Tables I, III, and IV). Multiple doses of empagliflozin 25 mg and HCTZ 25 mg or TOR 5 mg alone and in combination were well tolerated. The most common AE observed in this study was thirst, which was reported during combination therapy with empagliflozin plus a diuretic and was considered related to fluid restrictions imposed in accordance with the diuretic treatment. A limitation of our study is that these findings with HCTZ or TOR might not be applicable to other thiazide or loop diuretics. One strength of our study is that we assessed multiple doses to evaluate potential drugdrug interactions at steady state; therefore, drug exposure is expected to be similar after long-term treatment.
CONCLUSIONS Based on pharmacokinetic profiles, no drugdrug interactions were observed between empagliflozin and the diuretic agents HCTZ or TOR in patients with T2DM. Multiple doses of empagliflozin 25 mg and HCTZ 25 mg or TOR 5 mg alone and in combination were well tolerated.
ACKNOWLEDGMENTS The authors would like to acknowledge Lois Rowland for support with bioanalytical analyses and Jeanette Garcia for pharmacokinetic analyses. Assays for plasma and urine concentrations of empagliflozin, HCTZ, and TOR were performed by Bioanalytical Systems, Inc., West Lafayette, Indiana. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Clare Ryles and Elizabeth Ng 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.
802
CONFLICTS OF INTEREST Tim Heise is shareholder of a private research institute (Profil Institut für Stoffwechselforschung GmbH). Within the last year, this institute received research grants from the following pharmaceutical companies: Adocia, Astra Zeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Grünenthal, Eli Lilly and Company, Medtronic, Novo Nordisk, Novartis, Sanofi, Senseonics. Tim Heise has received travel grants, consulting fees and speaker honoraria from Eli Lilly and Company, Mylan and Novo Nordisk. Michaela Mattheus, Hans J. Woerle and Uli C. Broedl are employees of Boehringer Ingelheim. Sreeraj Macha was an employee of Boehringer Ingelheim at the time the study was conducted.
REFERENCES 1. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90. 2. Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15:613–621. 3. Seman L, Macha S, Nehmiz G, et al. Empagliflozin (BI 10773), a potent and selective SGLT-2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clinical Pharm in Drug Dev. 2013;2:152–161. 4. Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a randomised, 24-week, double-blind, placebo-controlled, parallel group, trial with sitagliptin as active comparator. Lancet Diabetes Endocrinol. 2013;1:208–219. 5. Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebocontrolled trial. Diabetes Obes Metab. 2014;16:147–158. 6. Häring H-U, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebocontrolled trial. Diabetes Care. 2014;37:1650–1659. 7. Häring H-U, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396–3404. 8. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes
Volume 37 Number 4
T. Heise et al.
9.
10.
11.
12.
13.
14.
treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:369– 384. Kabakov E, Norymberg C, Osher E, et al. Prevalence of hypertension in type 2 diabetes mellitus: impact of the tightening definition of high blood pressure and association with confounding risk factors. J Cardiometab Syndr. 2006;1:95– 101. Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive medication use and blood pressure control among united states adults with hypertension: the National Health and Nutrition Examination Survey, 2001 to 2010. Circulation. 2012;126:2105–2114. Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med. 2007;167:141–147. Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds. Expert Opin Drug Saf. 2010;9:243–257. Knauf H, Mutschler E. Clinical pharmacokinetics and pharmacodynamics of torasemide. Clin Pharmacokinet. 1998;34:1–24. Neugebauer G, Besenfelder E, von Möllendorff E. Pharmacokinetics and metabolism of torasemide in man. Arzneimittelforschung. 1988;38:164–166.
Address correspondence to: Tim Heise, MD, Profil Institut für Stoffwechselforschung GmbH, Hellersbergstrasse 9, Neuss, Germany. E-mail: tim. heise@profil.com
April 2015
803