- Email: [email protected]
Metformin Extended‐release Fixed‐dose Combination Tablets Relative to Single‐component Dapagliflozin and Metformin Extended‐release Tablets in Healthy Subjects
Clinical Therapeutics/Volume ], Number ], 2015
Bioequivalence, Food Effect, and Steady‐State Assessment of Dapagliflozin/Metformin Extended‐Release Fixed‐Dose Combination Tablets Relative to Single‐Component Dapagliflozin and Metformin Extended‐Release Tablets in Healthy Subjects Ming Chang, MS1; Xiaoni Liu, PhD1; Dapeng Cui, PhD2; Dan Liang, MS2; Frank LaCreta, PhD1; Steven C. Griffen, MD1,†; Susan Lubin, MA1; Donette Quamina-Edghill, MS1; and David W. Boulton, PhD1 1
Bristol-Myers Squibb, Princeton, New Jersey; and 2ICON Development Solutions, San Antonio, Texas
ABSTRACT Purpose: Simplification of therapeutic regimens for patients with type 2 diabetes mellitus can provide convenience that leads to improved compliance. Dapagliflozin/metformin extended-release (XR) fixeddose combination (FDC) tablets offer the convenience of once-daily dosing. Two pharmacokinetic (PK) studies were conducted to establish bioequivalence for 2 doses of dapagliflozin/metformin XR FDC versus the same dosage of the individual component (IC) tablets in healthy adults. Methods: Two open-label, randomized, 4-period, 4-arm crossover studies were conducted to assess the bioequivalence and PK properties of dapagliflozin and metformin FDCs in healthy subjects under fed and fasting conditions. Participants received single oral doses or once-daily dosing of dapagliflozin/metformin XR (5 mg/500 mg [study 1] or 10 mg/1000 mg [study 2]) for 4 days in an FDC formulation or corresponding strengths of IC tablets. Findings: For both of the studies, dapagliflozin and metformin 5 mg/500 mg or 10 mg/1000 mg FDC tablets were bioequivalent to the respective IC tablets. The 90% CIs of the ratio of the adjusted geometric means for all key PK parameters (Cmax, AUC0–T, and AUC0–1) were contained within the predefined 0.80 to 1.25 range to conclude bioequivalence for both dapagliflozin and metformin. Once-daily dosing to steady state of each FDC tablet had no effect on the PK properties of dapagliflozin or metformin. When
the FDCs were administered with a light-fat meal, there was no effect on metformin PK values and only a modest, nonclinically meaningful effect on dapagliflozin PK values. There were no safety or tolerability concerns. Implications: Bioequivalence of the FDCs of dapagliflozin/metformin XR and the ICs was established, and no safety issues of clinical concern were raised. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: bioequivalence, dapagliflozin, metformin XR, pharmacokinetics, SGLT2 inhibitor, type 2 diabetes mellitus.
INTRODUCTION In addition to dietary and lifestyle advice, metformin as immediate-release and extended-release (XR) tablets1 is the mainstay first-line treatment for type 2 diabetes mellitus (T2DM). As β-cell dysfunction progresses, however, patients generally need additional antihyperglycemic therapy, with most eventually needing to progress to insulin therapy to achieve glycemic goals.2 Not surprisingly, this use of several agents increases the complexity of treatment regimens, particularly when the dosing schedules and/or formulations are different. The availability of an insulin-independent antidiabetic agent in the T2DM Accepted for publication May 6, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.004 0149-2918/$ - see front matter
†
Current affiliation: Juvenile Diabetes Research Foundation, New York, New York.
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& 2015 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics therapy arsenal may support the achievement of treatment goals through the combination of agents with different mechanisms of action by reducing hyperglycemia before the need for insulin arises.3 Treatment with metformin acts to lower blood glucose levels primarily via effects on hepatic output of glucose (gluconeogenesis), glucose absorption from the intestine, and by improving insulin sensitivity in peripheral tissues.1 In usual monotherapy, neither formulation of metformin causes hypoglycemia, with exceptions for instances of insufficient caloric intake and alcohol use or in elderly or debilitated patients. Administration of sodium glucose cotransporter 2 (SGLT2) inhibitors results in blood glucose lowering by inhibition of renal glucose uptake, which leads to glycosuria. Dapagliflozin is an orally active, highly selective, reversible SGLT2 inhibitor that acts through this non– insulin-dependent mechanism.4 A review by Katsiki et al3 examined numerous studies which demonstrated that dapagliflozin reduces hyperglycemia,5–7 blood pressure,8 and weight9 by inhibiting renal glucose reabsorption. Fixed-dose combination (FDC) formulations of Z2 therapeutic agents with complementary mechanisms of action are increasingly used in the clinical setting because they simplify dosing regimens and improve adherence in patients who may need to take a number of therapeutic agents to maintain glycemic control.10 The differing mechanisms of action, as well as other pharmacologic properties of metformin and dapagliflozin, provide a rationale for using the FDC formulations of these agents for the treatment of diabetes. FDC formulations of dapagliflozin and metformin are thus currently under investigation. Two pharmacokinetic (PK) studies were conducted to establish the bioequivalence of dapagliflozin and metformin XR FDC tablets (dapagliflozin 5 mg/metformin XR 500 mg; dapagliflozin 10 mg/metformin XR 1000 mg) and the equivalent individual component (IC) tablets in healthy adults. Assessments were made in subjects receiving a single oral dose of an FDC of dapagliflozin/metformin XR and the IC tablets in the fed state to assess bioequivalence. FDCs were also assessed in subjects in the fasted state to investigate the effect of food and in subjects receiving a once-daily oral dose of each FDC for 4 days to investigate steady-state PK in the fed state. The results provide pivotal biopharmaceutical information supporting the clinical safety and efficacy data from Phase III studies in which dapagliflozin and metformin were administered together.
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SUBJECTS AND METHODS The 2 studies evaluating the bioequivalence of the dapagliflozin/metformin XR FDC tablets compared with the IC tablets at equivalent dosages were conducted in the United States during January and February 2012. Study 1 assessed the dapagliflozin/metformin XR 5 mg/500 mg FDC tablet (study number MB102100); study 2 assessed the dapagliflozin/metformin XR 10 mg/ 1000 mg FDC tablet (study number MB102092). The primary objective of the studies was to demonstrate the bioequivalence of dapagliflozin/metformin XR FDC tablets to the IC tablets in the fed state. The fed state was used because it is recommended that metformin XR should be taken with an evening meal.1 A lightfat meal was chosen because this is the type of meal recommended for patients with T2DM. The steady-state PK properties of dapagliflozin and metformin XR were also assessed after administration of the FDC tablet once daily for 4 days in the fed state (compared with a single dose in the fed state) to assess the consistency of the PK performance of the formulations. Single doses of the FDCs were assessed in the fasted state to assess the effect of food. The safety and tolerability of the XR FDC tablets and individual components were also analyzed.
Study Population Subjects who qualified for inclusion were healthy men and women, as determined by physical examination, vital signs, 12-lead ECG, and clinical laboratory values. Eligible subjects had to be aged between 18 and 55 years with a body mass index of 18 to 32 kg/m2. Women of childbearing potential were required to be using contraception and not be pregnant or breastfeeding; all women were required to have had a negative pregnancy test result within the 24 hours before the start of study medication. Sexually active men were required to use effective birth control throughout the entire study and for 90 days after the last date of treatment if their partners were women of childbearing potential. Key exclusion criteria included the following: any significant acute or chronic medical illness (within 2 months before study drug administration); evidence of organ dysfunction from physical findings or laboratory results; current or recent (within 3 months of study drug administration) gastrointestinal surgery or disease that could potentially affect study drug absorption; major surgery within 4 weeks of study drug administration; history of allergic reactions to metformin or dapagliflozin; intolerance to metformin or allergy or intolerance to
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M. Chang et al. similar agents; use of tobacco- or nicotine-containing products within 6 months of the study or a positive nicotine test result; and recent (within 6 months) drug and/or alcohol abuse. Subjects were instructed and agreed to refrain from strenuous exercise, contact sports, and sunbathing for the duration of the study. Subjects were not permitted to consume products or beverages containing alcohol, grapefruit, or caffeine from 3 days before the first dose of study drug until study discharge.
Study Designs Both studies were approved by the institutional review boards and were performed in accordance with Good Clinical Practice Guideline and the ethical principles underlying European Union Directive 2001/EC and 21 CFR 50. All subjects gave written informed consent before study initiation.
Study 1: Dapagliflozin/Metformin XR 5 mg/500 mg FDC Bioequivalence, Food Effect Study, and SteadyState PK Study 1 was an open-label, randomized, 4-period, 4-treatment, single-center crossover study in healthy
Period 2
Period 1 Treatment A Treatment B Treatment C
fasted and fed subjects. The study was 40 days in duration, including a 21-day screening period. Patients were randomized to 1 of 4 treatments: treatment A, single oral dose of dapagliflozin 5 mg and metformin XR 500 mg IC tablets administered in the fed state; treatment B, single oral dose of a dapagliflozin/ metformin XR 5 mg/500 mg FDC tablet administered in the fed state; treatment C, single oral dose of a dapagliflozin/metformin XR 5 mg/500 mg FDC tablet administered in the fasted state; and treatment D, once-daily doses of dapagliflozin/metformin XR 5 mg/ 500 mg FDC tablets administered in the fed state for 4 days. Treatments A, B, and D were administered 30 minutes after the start of a light-fat meal (containing 328–343 calories). Thirty-six subjects were randomized to 1 of 6 sequences (Figure 1). Subjects randomized to sequences ABC, BCA, or CAB subsequently received treatment D to assess the steady-state PK parameters of the XR FDC tablet. These subjects received treatment D in period 4, 48.5 hours after dosing in period 3. Periods 1 through 3 lasted for 2 days, and period 4 lasted for 5 days. There was a minimum
W W W
Treatment B Treatment C Treatment A
W W W
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Treatment D
D
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Treatment D
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Treatment B
Treatment D
D
S–R Treatment B Treatment C Treatment A
W W W
Treatment A Treatment B Treatment C
W W W
Treatment C
D
Treatment A
D
Treatment B
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Figure 1. Study design. Treatment A ¼ single oral dose of individual component (IC) tablets (study 1, one 5 mg dapagliflozin tablet and one 500 mg metformin extended-release [XR] tablet; study 2, one 10 mg dapagliflozin tablet and two 500 mg metformin XR tablets) administered in the fed state. Treatment B ¼ single oral dose of the fixed-dose combination (FDC) tablet (study 1, dapagliflozin 5 mg/metformin 500 mg XR; study 2, dapagliflozin 10 mg/metformin 1000 mg XR) administered in the fed state. Treatment C ¼ single oral dose of the FDC tablet (study 1, dapagliflozin 5 mg/metformin 500 mg XR; study 2, dapagliflozin 10 mg/metformin 1000 mg XR) administered in the fasted state. Treatment D ¼ once-daily oral doses of the FDC tablet (study 1, dapagliflozin 5 mg/metformin 500 mg XR; study 2, dapagliflozin 10 mg/metformin 1000 mg XR) administered in the fed state for 4 days. S ¼ screening up to 21 days; R ¼ randomization; W ¼ washout; D ¼ discharge.
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Clinical Therapeutics 4-day washout period between each dose in periods 1 through 3.
Study 2: Dapagliflozin/Metformin XR 10 mg/1000 mg FDC Bioequivalence, Food Effect Study, and SteadyState PK Study 2 was conducted with a design identical to study 1, except that it was conducted with dapagliflozin/metformin XR 10 mg/1000 mg FDC and dapagliflozin 10 mg and metformin 1000 mg XR (two 500 mg XR tablets) as IC.
Blood Sampling In the single-dose PK assessments in periods 1, 2, and 3 of both studies, blood samples were collected predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose. In period 4 of both studies, for the PK assessments in the steady state after multiple doses, blood samples were collected predose on days 2 and 3, on day 4 predose, and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. For determination of plasma dapagliflozin and metformin concentrations, whole blood was collected by direct venipuncture through an indwelling catheter into 3-mL dipotassium EDTA Vacutainers (BD Diagnostics, Franklin Lakes, New Jersey) and kept on ice. Within 1 hour of collection, plasma was prepared by centrifugation (15 minutes at 1000 g) and then stored at or below –20oC until analysis.
Bioanalytical Methods The plasma concentrations of dapagliflozin were determined by using a validated LC-MS/MS method, performed by Worldwide Clinical Trials Drug Development Solutions (Austin, Texas). In both studies, the method used for quantifying dapagliflozin was validated for a range of 1 to 200 ng/mL based on the analysis of 0.150 mL of plasma. The %CVs for between runs and within runs were r4.7% and r8.1%, respectively. Plasma concentrations of metformin were determined by using a validated LC-MS/MS method performed by PPD (Richmond, Virginia). Samples from both studies were analyzed for metformin within a nominal range or 2 to 2000 ng/mL. The %CVs for between runs and within runs were r6.79% and r21.4%, respectively.
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PK Methods Plasma PK parameters for dapagliflozin and metformin were calculated from plasma concentration– time data by using noncompartmental techniques (WinNonlin Professional Network Edition, version 5.2; Pharsight Corporation, Sunnyvale, California) and actual blood collection sampling times. Singledose PK parameters derived from plasma concentration–time data included Cmax, Tmax, AUC0–T, AUC0–1, and t1/2. For the steady-state PK assessments, in addition to Cmax and Tmax, AUC from time 0 through 1 dosing interval (AUCτ) and trough plasma concentrations were derived from plasma concentration–time data. Bioequivalence of the FDC tablets to the IC tablets and the food effect was assessed on systemic exposure (Cmax, AUC0–T, and AUC0–1). Potency-corrected results were provided for the treatment B to treatment A ratios of geometric means (GMs) for Cmax, AUC0–1, and AUC0–T of dapagliflozin and metformin, respectively. These were calculated based on the measured content of the test (treatment B) and reference (treatment A) treatments by using the following formula: Potency correction ¼ log (reference treatment measured content/test treatment measured content) The potency correction was applied to the point estimates and 90% CIs for the treatment B to treatment A comparison.
Statistical Analysis All statistical tabulations and analyses were performed by using SAS version 9.1.3 (SAS Institute, Inc, Cary, North Carolina). Descriptive statistics were used for number of subjects (mean, SDs, %CVs, GMs, median, and minimum and maximum values). Point estimates and 90% CIs were calculated for the FDC versus the IC in the fed state and for the FDC in fed versus fasted subjects for the GM ratios for Cmax, AUC0–1, and AUC0–T. Estimates were constructed from fitting the general linear mixed models for logtransformed data, with treatment and period as fixed effects and measurements within subjects as repeated measurements. Potency-corrected results were provided for the treatment B to treatment A GM ratios for Cmax, AUC0–1, and AUC0–T of dapagliflozin and metformin. Bioequivalence could be concluded if the 90% CIs of the ratios of GMs for the FDC versus IC comparison were entirely contained within the
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M. Chang et al. interval of 0.80 and 1.25 for Cmax, AUC0–T, and AUC0–1 of both dapagliflozin and metformin XR. The sample size calculations for dapagliflozin and metformin assumed that the Cmax and AUC0–1 of dapagliflozin or metformin were log normally distributed with intrasubject SDs of log(Cmax) and log(AUC0–1) no greater than 0.21 and 0.1, respectively, for dapagliflozin, and 0.23 and 0.18, respectively, for metformin. If there was 0% to 5% difference between the bioavailability of dapagliflozin or metformin, a sample size of 32 subjects would provide 90% to 99% power to conclude bioequivalence with respect to Cmax and AUC0–1 of dapagliflozin or metformin, respectively. In addition, data from 32 subjects would provide at least 90% confidence that the estimated GM ratio for dapagliflozin Cmax or metformin Cmax with and without food would
be within 10% of the true population ratio and at least 90% confidence that the estimated GM ratio for dapagliflozin or metformin AUC0–1 with and without food was within 7% of the true population ratio. To allow for dropouts, a study population of 36 was used.
Safety Assessments The safety and tolerability of the FDC were assessed based on medical review of adverse events (AEs) and vital sign measurements, ECGs, physical examination, and clinical laboratory tests.
RESULTS Subject Demographic Characteristics A total of 36 subjects were enrolled and received study drug in each study. All subjects completed study 1,
Table I. Subject demographic characteristics. Variable Age, y Mean (SD) Range (min–max) Sex, no.(%) Male Female Race, n (%) White Black Native Hawaiian/Other Pacific Islander Other Ethnicity, n (%) Hispanic/Latino Not Hispanic/Latino Height, cm Mean (SD) Range (min–max) Weight kg* Mean (SD) Range (min–max) BMI, kg/m2* Mean (SD) Range (min–max)
Study 1 (n ¼ 36)
Study 2 (n ¼ 36)
41.3 (10.46) 19–55
39.4 (11.22) 20–55
22 (61.1) 14 (38.9)
27 (75) 9 (25)
25 (69.4) 9 (25.0) 0 2 (5.6)
21 13 1 1
(58.3) (36.1) (2.8) (2.8)
4 (11.1) 32 (88.9)
4 (11.1) 32 (88.9)
171.5 (10.81) 154–190
172 (12.38) 148–192
77.49 (13.99) 50.2–102.0
79.96 (14.112) 51.5–105.5
26.19 (3.09) 20.7–31.0
26.88 (3.041) 20.3–31.3
n ¼ number of nonmissing observations; min ¼ minimum; max ¼ maximum; BMI ¼ body mass index. * For study 1, the day 1 value was used as baseline for weight and BMI
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Clinical Therapeutics
Concentration (ng/mL)
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90 80 70 60 50 40 30 20 10 0
Concentration (ng/mL)
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24 28 Time (h)
32
36
40
44
48
900 800 700 600 500 400 300 200 100 0
TRT A TRT C
TRT B TRT D
Figure 2. Mean (SD) plasma concentrations over time in study 1 for (A) dapagliflozin and (B) metformin. TRT ¼ treatment.
and 1 subject withdrew from study 2 for personal reasons. Baseline and demographic characteristics are presented in Table I.
PK Comparison of FDC Tablets and IC Tablets in the Fed State In fed subjects, the mean plasma concentration– time profile for dapagliflozin (5 mg or 10 mg) was similar when the drug was administered either as the FDC or IC in both studies (Figure 2A, Figure 3A). Absorption of dapagliflozin was rapid, with peak plasma concentrations observed 2 hours after dosing, and elimination was multiphasic (Table II). Adjusted GM ratios of dapagliflozin Cmax, AUC0–T, and AUC0–1 in the fed state were similar for the FDC and IC tablets (90% CIs within 0.80–1.25 for all comparisons), indicating bioequivalence for dapagliflozin. Potency correction with the measured content
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of dapagliflozin also produced bioequivalent results (Table III). Median Tmax was 2 hours for all doses of the IC tablets and FDC in the fed state (Table II), indicating a similar rate of absorption. The mean plasma concentration–time profile of metformin was also similar after a single oral dose of 500 or 1000 mg metformin XR either as the FDC or IC formulation for fed subjects in both studies (Figure 2B, Figure 3B). Absorption was prolonged (peak level occurred 4 hours postdose), and elimination was multiphasic. Plasma PK parameters are shown in Table II. Adjusted GM ratios for metformin Cmax, AUC0–T, and AUC0–1 in the fed state were similar for the FDC and IC tablets (90% CIs within 0.80–1.25), indicating bioequivalence for metformin (Table III). Potency correction with the measured content of metformin produced bioequivalent results (Table II and III).
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TRT A
TRT B
TRT C
TRT D
Figure 3. Mean (SD) plasma concentrations over time in study 2 for (A) dapagliflozin and (B) metformin. TRT ¼ treatment.
Median Tmax was 4 hours in the fed state for all doses of the ICs and FDC.
Effect of Food on PK Properties of Dapagliflozin/ Metformin XR FDC The peak plasma concentrations of dapagliflozin were lower and occurred later in the fed state than in the fasted state after administration of the FDC at either dose (dapagliflozin/metformin XR 5 mg/500 mg or 10 mg/1000 mg) (Table II). Comparing the fed and fasted state for both FDC doses, in the fed state, the adjusted GM Cmax of dapagliflozin was lower, the adjusted GM AUC0–T and AUC0–1 were slightly reduced (Table III), and Tmax was delayed by 1 hour. There was no difference in the t1/2 of dapagliflozin between the fed and fasted states. For
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dapagliflozin, a reduction in Cmax and modest reductions in AUC0–T and AUC0–1 in the fed state compared with the fasted state were observed for the FDCs at both doses (by 34.1%, 9.5%, and 9.3%, and by 34.4%, 7.9%, and 7.8% for dapagliflozin/ metformin XR 5 mg/500 mg and 10 mg/1000 mg, respectively). The reductions in dapagliflozin AUC still met the usual criteria (90% CI for the treatment ratios of GMs between 0.80 and 1.25) for concluding bioequivalence. The mean t1/2 of metformin was similar for the FDC in fed or fasted subjects (10.6 vs 13.1 hours and 12.4 vs 12.9 hours for dapagliflozin/metformin XR 5 mg/500 mg and 10 mg/1000 mg, respectively). Fed and fasted GM ratios and 90% CIs for metformin Cmax, AUC0–T, and AUC0–1 were close to 1, and the corresponding 90% CIs had a narrow range
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Cmax (ng/mL), GM (%CV)
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Dapagliflozin Dapa 5 mg/Met XR 500 mg (study 1) IC single dose, fed (n ¼ 36*) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 36) FDC 5/500 multiple dose, fed (n ¼ 18) Dapa 10 mg /Met XR 1000 mg (study 2) IC single dose, fed (n ¼ 35) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 35) FDC multiple dose, fed (n ¼ 18) Metformin Dapa 5 mg/Met XR 500 mg (study 1) IC single dose, fed (n ¼ 36) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 36*) FDC multiple dose, fed (n ¼ 18) Dapa 10 mg/Met XR 1000 mg (study 2) IC single dose, fed (n ¼ 35) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 35) FDC multiple dose, fed (n ¼ 18)
Tmax (h), median (min–max)
t1/2 (h), Mean (SD)
AUC0–T (ng/mL/h), GM (%CV)
AUC0–α (ng/mL/h), GM (%CV)
224 (25) 228 (23) 252 (26)
238 (25)* 246 (23) 271 (25)
45.9 46.5 70.6 51.6
(25) (27) (25) (21)
2.00 2.00 1.00 2.00
(0.5–3.03) (0.52–3.02) (0.48–2.00) (0.50–3.00)
9.03 (4.80) 10.2 (7.75) 10.2 (5.48)
99.9 93.7 142 92.5
(27) (28) (34) (24)
2.00 2.00 0.53 2.00
(1.00–4.02) (1.00–4.02) (0.50–1.05) (1.00–3.00)
11.3 (5.83) 11.3 (4.61) 11.3 (4.86)
647 631 608 623
(23) (22) (31) (24)
4.00 4.00 4.00 4.00
(3.00–6.03) (3.00–6.03) (3.00–4.05) (3.00–8.00)
11.2 (7.82) 10.6 (9.07) 13.1 (9.22)*
1100 1100 1080 1180
(27) (33) (25) (18)
4.00 4.00 3.03 4.00
(3.00–6.00) (3.00–8.03) (2.00–4.03) (3.00–6.00)
11.1 (6.46) 12.4 (6.91) 12.9 (7.03)
AUCτ (ng/mL/h), GM (%CV)
272 (22) 475 (28) 464 (26) 501 (29)
501 (28) 489 (27) 528 (29) 507 (27)
4971 (31) 4878 (25) 4820 (30)
5121 (31) 5042 (25) 4992 (30)* 5188 (28)
8980 (31) 8730 (33) 8290 (21)
9290 (30) 8970 (33) 8740 (22) 9550 (24)
GM ¼ geometric mean; Min ¼ minimum; Max ¼ maximum; AUCτ ¼ AUC from time 0 through 1 dosing interval; Dapa ¼ dapagliflozin; Met ¼ metformin; XR ¼ extended release; IC ¼ individual component; FDC ¼ fixed-dose combination. * AUC0–1 and t1/2 data of 1 subject were excluded from the summary of treatment due to AUC extrapolated 420%.
Clinical Therapeutics
8 Table II. Plasma pharmacokinetic parameters
M. Chang et al.
Table III. Bioequivalence and food effect Ratio (90% CI) of Adjusted GMs Variable Dapagliflozin Dapa 5 mg/Met XR 500 mg (study 1) FDC/IC, fed 1.012 FDC/IC, fed (potency corrected)* 1.027 FDC fed/fasted 0.659 Dapa 10 mg/Met XR 1000 mg (study 2) FDC/IC, fed 0.937 0.927 FDC/IC, fed (potency corrected)† FDC fed/fasted 0.656 Metformin Dapa 5 mg/Met XR 500 mg (study 1) FDC/IC, fed 0.975 0.957 FDC/IC, fed (potency corrected)‡ FDC fed/fasted 1.037 Dapa 10 mg/Met XR 1000 mg (study 2) FDC/IC, fed 1.001 0.983 FDC/IC, fed (potency corrected)§ FDC fed/fasted 1.016
AUC0–T
AUC0–1
(0.944–1.086) (0.957–1.101) (0.614–0.706)
1.018 (0.990–1.047) 1.032 (1.004–1.062) 0.905 (0.880–0.931)
1.019 (0.988–1.050) 1.033 (1.002–1.065) 0.907 (0.884–0.931)
(0.868–1.010) (0.860–1.000) (0.605–0.711)
0.972 (0.950–0.995) 0.963 (0.940–0.985) 0.921 (0.900–0.941)
0.971 (0.948–0.995) 0.961 (0.938–0.985) 0.922 (0.902–0.942)
(0.920–1.032) (0.903–1.014) (0.949–1.133)
0.981 (0.928–1.038) 0.964 (0.911–1.019) 1.012 (0.948–1.080)
0.985 (0.930–1.042) 0.967 (0.914–1.023) 0.990 (0.926–1.059)
(0.957–1.047) (0.940–1.028) (0.926–1.114)
0.974 (0.921–1.031) 0.957 (0.905–1.012) 1.054 (0.980–1.134)
0.979 (0.927–1.034) 0.961 (0.910–1.015) 1.026 (0.959–1.099)
Cmax
GM ¼ geometric mean; Dapa ¼ dapagliflozin; Met ¼ metformin; XR ¼ extended release; FDC ¼ fixed-dose combination; IC ¼ individual component. Potency-corrected results obtained by multiplying the adjusted GM ratio and 90% CI by the correction factor (correction factor ¼ measured content of reference treatment/measured content of test treatment). * Correction factor 4.98/4.91 ¼ 1.014. † Correction factor 9.9/10 ¼ 0.99. ‡ Correction factor 489/498 ¼ 0.982. § Correction factor 978/996 ¼ 0.982.
(0.9–1.2), indicating little or no food effect for metformin when either dose of the FDC was administered.
PK Assessment of Multiple Doses versus Single Doses in the Fed State When FDC dapagliflozin/metformin XR 5 mg/500 mg or 10 mg/1000 mg was administered as a single dose in the fed state, the GM Cmax of dapagliflozin was 46.5 and 93.7 ng/mL, respectively. After 4 days of once-daily dosing with either dose, the GM Cmax of dapagliflozin was 51.6 and 92.5 ng/mL, respectively, indicating little if any accumulation. The GM AUCτ of dapagliflozin after repeated dosing (272 ng/mL/h) was similar to the GM AUC0–1 after a single dose ] 2015
(246 ng/mL/h) of FDC dapagliflozin/metformin XR 5 mg/500 mg; the same was true with the 10 mg/1000 mg FDC (507 vs 489 ng/mL/h) (Table II). After 4 days of administration of the FDC at either dose in the fed state, the 0- to 24-hour mean plasma profile of dapagliflozin was slightly higher compared with the mean profile after single-dose administration, indicating modest accumulation with multiple dosing. After once-daily dosing with either dose of the FDC, GM trough plasma dapagliflozin concentrations increased slightly (day 2–day 5). After 4 days of once-daily administration of either dose of the FDC in the fed state, the 0- to 24-hour mean plasma profile of metformin was slightly higher compared with the mean profile after single-dose
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Clinical Therapeutics administration, with no evidence of “dose dumping” (ie, the unexpectedly rapid release of drug from an XR formulation). After once-daily dosing with either dose of the FDC in the fed state, GM trough plasma metformin concentrations increased slightly from day 2 to day 5. After 4 days of once-daily FDC dosing (dapagliflozin/metformin XR 5 mg/500 mg or 10 mg/ 1000 mg) in the fed state, Cmax and Tmax for metformin were similar to the corresponding values after single-dose administration (Table II). The GM AUCτ for metformin after repeated dosing was similar to the GM AUC0–1 after a single dose.
Safety and Tolerability Profile Generally, both FDCs were well tolerated in the fed and fasted state, as single oral doses or after oncedaily dosing for 4 days. There were no deaths, serious AEs, or clinically significant laboratory abnormalities, and vital signs and physical examination findings were normal. There were no discontinuations due to AEs. In study 1, a total of 18 subjects reported 55 AEs. Headache was the most common AE and occurred in 16.7% of subjects; the incidence was similar with all treatments but slightly higher in the fasted state. Most AEs were considered by the investigator not to be study drug related. Two moderate AEs (headache and feeling hot) occurred. In study 2, a total of 10 subjects reported 17 AEs (6 were considered related to study drug); the incidence was similar for single doses of treatments in the fed state but slightly higher for treatment in the fasted state. For all treatments, gastrointestinal AEs were the most common (13.9%); 2 subjects experienced abdominal pain. One moderate AE (urinary tract infection) was reported with FDC dapagliflozin/ metformin XR 10/1000 mg in the fed state; it resolved with antibiotic treatment (ciprofloxacin). No moderate events were documented in the other study arms.
DISCUSSION The addition of dapagliflozin to the treatment regimen for patients with T2DM who have inadequate glycemic control on metformin alone results in significant reductions in glycosylated hemoglobin, with a low risk of hypoglycemia and an adequate safety and tolerability profile.3,5–7 The results reported here establish the PK findings and bioequivalence of an FDC of dapagliflozin/metformin XR (5 mg/500 mg and 10 mg/1000 mg) to the corresponding IC in the
10
fed state in healthy adults. Across-study analyses have shown that the PK values of dapagliflozin and metformin are comparable between healthy subjects and patients with T2DM with normal renal function. Thus, the findings of this study in healthy subjects may be translatable to patients with T2DM.11,12 Assessment of the impact of food on the bioavailability of dapagliflozin in FDC formulations with metformin did not identify a meaningful food effect. Because the cumulative amount of glucose excreted in the urine, and hence dapagliflozin efficacy, are dependent upon AUC and not peak concentration as determined by Cmax,13 the reduction of dapagliflozin Cmax under fed conditions (dapagliflozin 5 mg/ metformin XR 500 mg, 34.1% reduction; dapagliflozin 10 mg/metformin XR 1000 mg, 34.4% reduction) is unlikely to be clinically meaningful. Therefore, patients should be able to take the FDC of dapagliflozin/metformin without regard to meals. This effect was consistent with earlier findings from Kasichayanula et al.13 Single- and multiple-dose PK findings for both dapagliflozin and metformin were similar with either dose of the FDC, and only slight accumulations of dapagliflozin and metformin were observed. This is consistent with previous findings for metformin.14 Dose dumping is an important consideration in the development of XR dosage forms. The phenomenon happens when an unintended bolus or rapid release of drug occurs from a modified-release formulation, often in association with food or coingestion of ethanol.15 This study found no evidence of dose dumping during the multiple-dose assessment period, indicating that the performance of the XR metformin component is unaffected by formulation into a once-daily FDC with dapagliflozin. In T2DM, the use of FDCs offers several advantages over the use of ICs; the convenience of oncedaily dosing and a lower daily tablet burden could potentially lead to reduced cost to the patient (1 prescription compared with 2) and improved adherence to treatment.10 An XR FDC of dapagliflozin and metformin has the potential to provide these benefits to patients with T2DM. Recently, several other antidiabetic or related therapeutic agents have been developed into FDCs, including saxagliptin/metformin XR and atorvastatin/ metformin XR.16,17 Establishing a treatment strategy that incorporates FDCs may simplify diabetes
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M. Chang et al. treatment regimens and support the management of concurrent conditions also requiring drug treatment by reducing the pill burden on patients. There were no unexpected or unusual safety or tolerability concerns with the FDC or the IC tablets in single doses administered to healthy adults, in the fed or fasting states or with the FDC in multiple doses in the fed state in either study.
CONCLUSIONS Bioequivalence of both dapagliflozin and metformin was established between the XR FDC tablets and the IC tablets with either dose when administered in the fed state and for both doses of the FDC of dapagliflozin/metformin between the fed and fasted state. The PK values of dapagliflozin or metformin were not changed at either dose of the FDC by repeated oncedaily dosing over 4 days, and there was no evidence of dose dumping during the dosing period. There were no apparent safety or tolerability concerns with the XR FDC tablets at either dose when administered to healthy subjects in the fed or fasted state. These results support the validity of the FDC of dapagliflozin/ metformin for the treatment of T2DM, as bioequivalence was established and the PK properties of dapagliflozin and metformin were not changed by multiple dosing over 4 days.
ACKNOWLEDGMENTS The study was sponsored by Bristol-Myers Squibb and AstraZeneca. The authors thank Sreeneeranj Kasichayanula for his contributions to this study. Medical writing assistance was provided by Ray Ashton and Lisa Bergstrom of PPSI (a PAREXEL company), funded by AstraZeneca. Each author made a material contribution to the manuscript through development of content and review during drafting of the manuscript. All authors provided approval of the final article.
CONFLICTS OF INTEREST Mr. Chang, Dr. Liu, Dr. LaCreta, Dr. Griffen, Ms. Lubin, Ms. Quamina‐Edghill, and Dr. Boulton are stockholders and/or employees of Bristol-Myers Squibb. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
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REFERENCES 1. Glucophage [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2009. 2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577–1596. 3. Katsiki N, Papanas N, Mikhailidis DP. Dapagliflozin: more than just another oral glucose-lowering agent? Expert Opin Investig Drugs. 2010;19:1581–1589. 4. Meng W, Ellsworth BA, Nirschl AA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008;51:1145–1149. 5. List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–657. 6. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–2233. 7. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–2224. 8. Wilding JP, Norwood P, T'joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32: 1656–1662. 9. Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–1031. 10. Bell DS. Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. Diabetes Obes Metab. 2013;15:291–300. 11. Kasichayanula S, Liu X, Lacreta F, et al. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014;53:17–27. 12. Duong JK, Kumar SS, Kirkpatrick CM, et al. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clin Pharmacokinet. 2013; 52:373–384. 13. Kasichayanula S, Liu X, Zhang W, et al. Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects. Diabetes Obes Metab. 2011;13:770–773.
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Clinical Therapeutics 14. Timmins P, Donahue S, Meeker J, Marathe P. Steady-state pharmacokinetics of a novel extendedrelease metformin formulation. Clin Pharmacokinet. 2005;44:721– 729. 15. Hendeles L, Weinberger M. Selection of a slow-release theophylline product. J Allergy Clin Immunol. 1986;78:743–751. 16. Boulton DW, Smith CH, Li L, et al. Bioequivalence of saxagliptin/metformin extended-release (XR) fixeddose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects. Clin Drug Investig. 2011;31:619–630. 17. Kandhwal K, Dey S, Nazarudheen S, et al. Pharmacokinetics of a fixeddose combination of atorvastatin and metformin extended release versus concurrent administration of individual formulations: a randomized, open-label, two-treatment, two-period, two-sequence, singledose, crossover, bioequivalence study. Clin Drug Investig. 2011;31: 853–863.
Address correspondence to: David W. Boulton, PhD, PO Box 4000, Bristol‐Myers Squibb, Princeton, NJ 08543‐4000. E-mail: [email protected]
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Bioequivalence, Food Effect, and Steady‐State Assessment of Dapagliflozin/Metformin Extended‐Release Fixed‐Dose Combination Tablets Relative to Single‐Component Dapagliflozin and Metformin Extended‐Release Tablets in Healthy Subjects Ming Chang, MS1; Xiaoni Liu, PhD1; Dapeng Cui, PhD2; Dan Liang, MS2; Frank LaCreta, PhD1; Steven C. Griffen, MD1,†; Susan Lubin, MA1; Donette Quamina-Edghill, MS1; and David W. Boulton, PhD1 1
Bristol-Myers Squibb, Princeton, New Jersey; and 2ICON Development Solutions, San Antonio, Texas
ABSTRACT Purpose: Simplification of therapeutic regimens for patients with type 2 diabetes mellitus can provide convenience that leads to improved compliance. Dapagliflozin/metformin extended-release (XR) fixeddose combination (FDC) tablets offer the convenience of once-daily dosing. Two pharmacokinetic (PK) studies were conducted to establish bioequivalence for 2 doses of dapagliflozin/metformin XR FDC versus the same dosage of the individual component (IC) tablets in healthy adults. Methods: Two open-label, randomized, 4-period, 4-arm crossover studies were conducted to assess the bioequivalence and PK properties of dapagliflozin and metformin FDCs in healthy subjects under fed and fasting conditions. Participants received single oral doses or once-daily dosing of dapagliflozin/metformin XR (5 mg/500 mg [study 1] or 10 mg/1000 mg [study 2]) for 4 days in an FDC formulation or corresponding strengths of IC tablets. Findings: For both of the studies, dapagliflozin and metformin 5 mg/500 mg or 10 mg/1000 mg FDC tablets were bioequivalent to the respective IC tablets. The 90% CIs of the ratio of the adjusted geometric means for all key PK parameters (Cmax, AUC0–T, and AUC0–1) were contained within the predefined 0.80 to 1.25 range to conclude bioequivalence for both dapagliflozin and metformin. Once-daily dosing to steady state of each FDC tablet had no effect on the PK properties of dapagliflozin or metformin. When
the FDCs were administered with a light-fat meal, there was no effect on metformin PK values and only a modest, nonclinically meaningful effect on dapagliflozin PK values. There were no safety or tolerability concerns. Implications: Bioequivalence of the FDCs of dapagliflozin/metformin XR and the ICs was established, and no safety issues of clinical concern were raised. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: bioequivalence, dapagliflozin, metformin XR, pharmacokinetics, SGLT2 inhibitor, type 2 diabetes mellitus.
INTRODUCTION In addition to dietary and lifestyle advice, metformin as immediate-release and extended-release (XR) tablets1 is the mainstay first-line treatment for type 2 diabetes mellitus (T2DM). As β-cell dysfunction progresses, however, patients generally need additional antihyperglycemic therapy, with most eventually needing to progress to insulin therapy to achieve glycemic goals.2 Not surprisingly, this use of several agents increases the complexity of treatment regimens, particularly when the dosing schedules and/or formulations are different. The availability of an insulin-independent antidiabetic agent in the T2DM Accepted for publication May 6, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.004 0149-2918/$ - see front matter
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Current affiliation: Juvenile Diabetes Research Foundation, New York, New York.
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& 2015 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics therapy arsenal may support the achievement of treatment goals through the combination of agents with different mechanisms of action by reducing hyperglycemia before the need for insulin arises.3 Treatment with metformin acts to lower blood glucose levels primarily via effects on hepatic output of glucose (gluconeogenesis), glucose absorption from the intestine, and by improving insulin sensitivity in peripheral tissues.1 In usual monotherapy, neither formulation of metformin causes hypoglycemia, with exceptions for instances of insufficient caloric intake and alcohol use or in elderly or debilitated patients. Administration of sodium glucose cotransporter 2 (SGLT2) inhibitors results in blood glucose lowering by inhibition of renal glucose uptake, which leads to glycosuria. Dapagliflozin is an orally active, highly selective, reversible SGLT2 inhibitor that acts through this non– insulin-dependent mechanism.4 A review by Katsiki et al3 examined numerous studies which demonstrated that dapagliflozin reduces hyperglycemia,5–7 blood pressure,8 and weight9 by inhibiting renal glucose reabsorption. Fixed-dose combination (FDC) formulations of Z2 therapeutic agents with complementary mechanisms of action are increasingly used in the clinical setting because they simplify dosing regimens and improve adherence in patients who may need to take a number of therapeutic agents to maintain glycemic control.10 The differing mechanisms of action, as well as other pharmacologic properties of metformin and dapagliflozin, provide a rationale for using the FDC formulations of these agents for the treatment of diabetes. FDC formulations of dapagliflozin and metformin are thus currently under investigation. Two pharmacokinetic (PK) studies were conducted to establish the bioequivalence of dapagliflozin and metformin XR FDC tablets (dapagliflozin 5 mg/metformin XR 500 mg; dapagliflozin 10 mg/metformin XR 1000 mg) and the equivalent individual component (IC) tablets in healthy adults. Assessments were made in subjects receiving a single oral dose of an FDC of dapagliflozin/metformin XR and the IC tablets in the fed state to assess bioequivalence. FDCs were also assessed in subjects in the fasted state to investigate the effect of food and in subjects receiving a once-daily oral dose of each FDC for 4 days to investigate steady-state PK in the fed state. The results provide pivotal biopharmaceutical information supporting the clinical safety and efficacy data from Phase III studies in which dapagliflozin and metformin were administered together.
2
SUBJECTS AND METHODS The 2 studies evaluating the bioequivalence of the dapagliflozin/metformin XR FDC tablets compared with the IC tablets at equivalent dosages were conducted in the United States during January and February 2012. Study 1 assessed the dapagliflozin/metformin XR 5 mg/500 mg FDC tablet (study number MB102100); study 2 assessed the dapagliflozin/metformin XR 10 mg/ 1000 mg FDC tablet (study number MB102092). The primary objective of the studies was to demonstrate the bioequivalence of dapagliflozin/metformin XR FDC tablets to the IC tablets in the fed state. The fed state was used because it is recommended that metformin XR should be taken with an evening meal.1 A lightfat meal was chosen because this is the type of meal recommended for patients with T2DM. The steady-state PK properties of dapagliflozin and metformin XR were also assessed after administration of the FDC tablet once daily for 4 days in the fed state (compared with a single dose in the fed state) to assess the consistency of the PK performance of the formulations. Single doses of the FDCs were assessed in the fasted state to assess the effect of food. The safety and tolerability of the XR FDC tablets and individual components were also analyzed.
Study Population Subjects who qualified for inclusion were healthy men and women, as determined by physical examination, vital signs, 12-lead ECG, and clinical laboratory values. Eligible subjects had to be aged between 18 and 55 years with a body mass index of 18 to 32 kg/m2. Women of childbearing potential were required to be using contraception and not be pregnant or breastfeeding; all women were required to have had a negative pregnancy test result within the 24 hours before the start of study medication. Sexually active men were required to use effective birth control throughout the entire study and for 90 days after the last date of treatment if their partners were women of childbearing potential. Key exclusion criteria included the following: any significant acute or chronic medical illness (within 2 months before study drug administration); evidence of organ dysfunction from physical findings or laboratory results; current or recent (within 3 months of study drug administration) gastrointestinal surgery or disease that could potentially affect study drug absorption; major surgery within 4 weeks of study drug administration; history of allergic reactions to metformin or dapagliflozin; intolerance to metformin or allergy or intolerance to
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M. Chang et al. similar agents; use of tobacco- or nicotine-containing products within 6 months of the study or a positive nicotine test result; and recent (within 6 months) drug and/or alcohol abuse. Subjects were instructed and agreed to refrain from strenuous exercise, contact sports, and sunbathing for the duration of the study. Subjects were not permitted to consume products or beverages containing alcohol, grapefruit, or caffeine from 3 days before the first dose of study drug until study discharge.
Study Designs Both studies were approved by the institutional review boards and were performed in accordance with Good Clinical Practice Guideline and the ethical principles underlying European Union Directive 2001/EC and 21 CFR 50. All subjects gave written informed consent before study initiation.
Study 1: Dapagliflozin/Metformin XR 5 mg/500 mg FDC Bioequivalence, Food Effect Study, and SteadyState PK Study 1 was an open-label, randomized, 4-period, 4-treatment, single-center crossover study in healthy
Period 2
Period 1 Treatment A Treatment B Treatment C
fasted and fed subjects. The study was 40 days in duration, including a 21-day screening period. Patients were randomized to 1 of 4 treatments: treatment A, single oral dose of dapagliflozin 5 mg and metformin XR 500 mg IC tablets administered in the fed state; treatment B, single oral dose of a dapagliflozin/ metformin XR 5 mg/500 mg FDC tablet administered in the fed state; treatment C, single oral dose of a dapagliflozin/metformin XR 5 mg/500 mg FDC tablet administered in the fasted state; and treatment D, once-daily doses of dapagliflozin/metformin XR 5 mg/ 500 mg FDC tablets administered in the fed state for 4 days. Treatments A, B, and D were administered 30 minutes after the start of a light-fat meal (containing 328–343 calories). Thirty-six subjects were randomized to 1 of 6 sequences (Figure 1). Subjects randomized to sequences ABC, BCA, or CAB subsequently received treatment D to assess the steady-state PK parameters of the XR FDC tablet. These subjects received treatment D in period 4, 48.5 hours after dosing in period 3. Periods 1 through 3 lasted for 2 days, and period 4 lasted for 5 days. There was a minimum
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Figure 1. Study design. Treatment A ¼ single oral dose of individual component (IC) tablets (study 1, one 5 mg dapagliflozin tablet and one 500 mg metformin extended-release [XR] tablet; study 2, one 10 mg dapagliflozin tablet and two 500 mg metformin XR tablets) administered in the fed state. Treatment B ¼ single oral dose of the fixed-dose combination (FDC) tablet (study 1, dapagliflozin 5 mg/metformin 500 mg XR; study 2, dapagliflozin 10 mg/metformin 1000 mg XR) administered in the fed state. Treatment C ¼ single oral dose of the FDC tablet (study 1, dapagliflozin 5 mg/metformin 500 mg XR; study 2, dapagliflozin 10 mg/metformin 1000 mg XR) administered in the fasted state. Treatment D ¼ once-daily oral doses of the FDC tablet (study 1, dapagliflozin 5 mg/metformin 500 mg XR; study 2, dapagliflozin 10 mg/metformin 1000 mg XR) administered in the fed state for 4 days. S ¼ screening up to 21 days; R ¼ randomization; W ¼ washout; D ¼ discharge.
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Clinical Therapeutics 4-day washout period between each dose in periods 1 through 3.
Study 2: Dapagliflozin/Metformin XR 10 mg/1000 mg FDC Bioequivalence, Food Effect Study, and SteadyState PK Study 2 was conducted with a design identical to study 1, except that it was conducted with dapagliflozin/metformin XR 10 mg/1000 mg FDC and dapagliflozin 10 mg and metformin 1000 mg XR (two 500 mg XR tablets) as IC.
Blood Sampling In the single-dose PK assessments in periods 1, 2, and 3 of both studies, blood samples were collected predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose. In period 4 of both studies, for the PK assessments in the steady state after multiple doses, blood samples were collected predose on days 2 and 3, on day 4 predose, and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. For determination of plasma dapagliflozin and metformin concentrations, whole blood was collected by direct venipuncture through an indwelling catheter into 3-mL dipotassium EDTA Vacutainers (BD Diagnostics, Franklin Lakes, New Jersey) and kept on ice. Within 1 hour of collection, plasma was prepared by centrifugation (15 minutes at 1000 g) and then stored at or below –20oC until analysis.
Bioanalytical Methods The plasma concentrations of dapagliflozin were determined by using a validated LC-MS/MS method, performed by Worldwide Clinical Trials Drug Development Solutions (Austin, Texas). In both studies, the method used for quantifying dapagliflozin was validated for a range of 1 to 200 ng/mL based on the analysis of 0.150 mL of plasma. The %CVs for between runs and within runs were r4.7% and r8.1%, respectively. Plasma concentrations of metformin were determined by using a validated LC-MS/MS method performed by PPD (Richmond, Virginia). Samples from both studies were analyzed for metformin within a nominal range or 2 to 2000 ng/mL. The %CVs for between runs and within runs were r6.79% and r21.4%, respectively.
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PK Methods Plasma PK parameters for dapagliflozin and metformin were calculated from plasma concentration– time data by using noncompartmental techniques (WinNonlin Professional Network Edition, version 5.2; Pharsight Corporation, Sunnyvale, California) and actual blood collection sampling times. Singledose PK parameters derived from plasma concentration–time data included Cmax, Tmax, AUC0–T, AUC0–1, and t1/2. For the steady-state PK assessments, in addition to Cmax and Tmax, AUC from time 0 through 1 dosing interval (AUCτ) and trough plasma concentrations were derived from plasma concentration–time data. Bioequivalence of the FDC tablets to the IC tablets and the food effect was assessed on systemic exposure (Cmax, AUC0–T, and AUC0–1). Potency-corrected results were provided for the treatment B to treatment A ratios of geometric means (GMs) for Cmax, AUC0–1, and AUC0–T of dapagliflozin and metformin, respectively. These were calculated based on the measured content of the test (treatment B) and reference (treatment A) treatments by using the following formula: Potency correction ¼ log (reference treatment measured content/test treatment measured content) The potency correction was applied to the point estimates and 90% CIs for the treatment B to treatment A comparison.
Statistical Analysis All statistical tabulations and analyses were performed by using SAS version 9.1.3 (SAS Institute, Inc, Cary, North Carolina). Descriptive statistics were used for number of subjects (mean, SDs, %CVs, GMs, median, and minimum and maximum values). Point estimates and 90% CIs were calculated for the FDC versus the IC in the fed state and for the FDC in fed versus fasted subjects for the GM ratios for Cmax, AUC0–1, and AUC0–T. Estimates were constructed from fitting the general linear mixed models for logtransformed data, with treatment and period as fixed effects and measurements within subjects as repeated measurements. Potency-corrected results were provided for the treatment B to treatment A GM ratios for Cmax, AUC0–1, and AUC0–T of dapagliflozin and metformin. Bioequivalence could be concluded if the 90% CIs of the ratios of GMs for the FDC versus IC comparison were entirely contained within the
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M. Chang et al. interval of 0.80 and 1.25 for Cmax, AUC0–T, and AUC0–1 of both dapagliflozin and metformin XR. The sample size calculations for dapagliflozin and metformin assumed that the Cmax and AUC0–1 of dapagliflozin or metformin were log normally distributed with intrasubject SDs of log(Cmax) and log(AUC0–1) no greater than 0.21 and 0.1, respectively, for dapagliflozin, and 0.23 and 0.18, respectively, for metformin. If there was 0% to 5% difference between the bioavailability of dapagliflozin or metformin, a sample size of 32 subjects would provide 90% to 99% power to conclude bioequivalence with respect to Cmax and AUC0–1 of dapagliflozin or metformin, respectively. In addition, data from 32 subjects would provide at least 90% confidence that the estimated GM ratio for dapagliflozin Cmax or metformin Cmax with and without food would
be within 10% of the true population ratio and at least 90% confidence that the estimated GM ratio for dapagliflozin or metformin AUC0–1 with and without food was within 7% of the true population ratio. To allow for dropouts, a study population of 36 was used.
Safety Assessments The safety and tolerability of the FDC were assessed based on medical review of adverse events (AEs) and vital sign measurements, ECGs, physical examination, and clinical laboratory tests.
RESULTS Subject Demographic Characteristics A total of 36 subjects were enrolled and received study drug in each study. All subjects completed study 1,
Table I. Subject demographic characteristics. Variable Age, y Mean (SD) Range (min–max) Sex, no.(%) Male Female Race, n (%) White Black Native Hawaiian/Other Pacific Islander Other Ethnicity, n (%) Hispanic/Latino Not Hispanic/Latino Height, cm Mean (SD) Range (min–max) Weight kg* Mean (SD) Range (min–max) BMI, kg/m2* Mean (SD) Range (min–max)
Study 1 (n ¼ 36)
Study 2 (n ¼ 36)
41.3 (10.46) 19–55
39.4 (11.22) 20–55
22 (61.1) 14 (38.9)
27 (75) 9 (25)
25 (69.4) 9 (25.0) 0 2 (5.6)
21 13 1 1
(58.3) (36.1) (2.8) (2.8)
4 (11.1) 32 (88.9)
4 (11.1) 32 (88.9)
171.5 (10.81) 154–190
172 (12.38) 148–192
77.49 (13.99) 50.2–102.0
79.96 (14.112) 51.5–105.5
26.19 (3.09) 20.7–31.0
26.88 (3.041) 20.3–31.3
n ¼ number of nonmissing observations; min ¼ minimum; max ¼ maximum; BMI ¼ body mass index. * For study 1, the day 1 value was used as baseline for weight and BMI
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Clinical Therapeutics
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Figure 2. Mean (SD) plasma concentrations over time in study 1 for (A) dapagliflozin and (B) metformin. TRT ¼ treatment.
and 1 subject withdrew from study 2 for personal reasons. Baseline and demographic characteristics are presented in Table I.
PK Comparison of FDC Tablets and IC Tablets in the Fed State In fed subjects, the mean plasma concentration– time profile for dapagliflozin (5 mg or 10 mg) was similar when the drug was administered either as the FDC or IC in both studies (Figure 2A, Figure 3A). Absorption of dapagliflozin was rapid, with peak plasma concentrations observed 2 hours after dosing, and elimination was multiphasic (Table II). Adjusted GM ratios of dapagliflozin Cmax, AUC0–T, and AUC0–1 in the fed state were similar for the FDC and IC tablets (90% CIs within 0.80–1.25 for all comparisons), indicating bioequivalence for dapagliflozin. Potency correction with the measured content
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of dapagliflozin also produced bioequivalent results (Table III). Median Tmax was 2 hours for all doses of the IC tablets and FDC in the fed state (Table II), indicating a similar rate of absorption. The mean plasma concentration–time profile of metformin was also similar after a single oral dose of 500 or 1000 mg metformin XR either as the FDC or IC formulation for fed subjects in both studies (Figure 2B, Figure 3B). Absorption was prolonged (peak level occurred 4 hours postdose), and elimination was multiphasic. Plasma PK parameters are shown in Table II. Adjusted GM ratios for metformin Cmax, AUC0–T, and AUC0–1 in the fed state were similar for the FDC and IC tablets (90% CIs within 0.80–1.25), indicating bioequivalence for metformin (Table III). Potency correction with the measured content of metformin produced bioequivalent results (Table II and III).
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TRT D
Figure 3. Mean (SD) plasma concentrations over time in study 2 for (A) dapagliflozin and (B) metformin. TRT ¼ treatment.
Median Tmax was 4 hours in the fed state for all doses of the ICs and FDC.
Effect of Food on PK Properties of Dapagliflozin/ Metformin XR FDC The peak plasma concentrations of dapagliflozin were lower and occurred later in the fed state than in the fasted state after administration of the FDC at either dose (dapagliflozin/metformin XR 5 mg/500 mg or 10 mg/1000 mg) (Table II). Comparing the fed and fasted state for both FDC doses, in the fed state, the adjusted GM Cmax of dapagliflozin was lower, the adjusted GM AUC0–T and AUC0–1 were slightly reduced (Table III), and Tmax was delayed by 1 hour. There was no difference in the t1/2 of dapagliflozin between the fed and fasted states. For
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dapagliflozin, a reduction in Cmax and modest reductions in AUC0–T and AUC0–1 in the fed state compared with the fasted state were observed for the FDCs at both doses (by 34.1%, 9.5%, and 9.3%, and by 34.4%, 7.9%, and 7.8% for dapagliflozin/ metformin XR 5 mg/500 mg and 10 mg/1000 mg, respectively). The reductions in dapagliflozin AUC still met the usual criteria (90% CI for the treatment ratios of GMs between 0.80 and 1.25) for concluding bioequivalence. The mean t1/2 of metformin was similar for the FDC in fed or fasted subjects (10.6 vs 13.1 hours and 12.4 vs 12.9 hours for dapagliflozin/metformin XR 5 mg/500 mg and 10 mg/1000 mg, respectively). Fed and fasted GM ratios and 90% CIs for metformin Cmax, AUC0–T, and AUC0–1 were close to 1, and the corresponding 90% CIs had a narrow range
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Cmax (ng/mL), GM (%CV)
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Dapagliflozin Dapa 5 mg/Met XR 500 mg (study 1) IC single dose, fed (n ¼ 36*) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 36) FDC 5/500 multiple dose, fed (n ¼ 18) Dapa 10 mg /Met XR 1000 mg (study 2) IC single dose, fed (n ¼ 35) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 35) FDC multiple dose, fed (n ¼ 18) Metformin Dapa 5 mg/Met XR 500 mg (study 1) IC single dose, fed (n ¼ 36) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 36*) FDC multiple dose, fed (n ¼ 18) Dapa 10 mg/Met XR 1000 mg (study 2) IC single dose, fed (n ¼ 35) FDC single dose, fed (n ¼ 36) FDC single dose, fasted (n ¼ 35) FDC multiple dose, fed (n ¼ 18)
Tmax (h), median (min–max)
t1/2 (h), Mean (SD)
AUC0–T (ng/mL/h), GM (%CV)
AUC0–α (ng/mL/h), GM (%CV)
224 (25) 228 (23) 252 (26)
238 (25)* 246 (23) 271 (25)
45.9 46.5 70.6 51.6
(25) (27) (25) (21)
2.00 2.00 1.00 2.00
(0.5–3.03) (0.52–3.02) (0.48–2.00) (0.50–3.00)
9.03 (4.80) 10.2 (7.75) 10.2 (5.48)
99.9 93.7 142 92.5
(27) (28) (34) (24)
2.00 2.00 0.53 2.00
(1.00–4.02) (1.00–4.02) (0.50–1.05) (1.00–3.00)
11.3 (5.83) 11.3 (4.61) 11.3 (4.86)
647 631 608 623
(23) (22) (31) (24)
4.00 4.00 4.00 4.00
(3.00–6.03) (3.00–6.03) (3.00–4.05) (3.00–8.00)
11.2 (7.82) 10.6 (9.07) 13.1 (9.22)*
1100 1100 1080 1180
(27) (33) (25) (18)
4.00 4.00 3.03 4.00
(3.00–6.00) (3.00–8.03) (2.00–4.03) (3.00–6.00)
11.1 (6.46) 12.4 (6.91) 12.9 (7.03)
AUCτ (ng/mL/h), GM (%CV)
272 (22) 475 (28) 464 (26) 501 (29)
501 (28) 489 (27) 528 (29) 507 (27)
4971 (31) 4878 (25) 4820 (30)
5121 (31) 5042 (25) 4992 (30)* 5188 (28)
8980 (31) 8730 (33) 8290 (21)
9290 (30) 8970 (33) 8740 (22) 9550 (24)
GM ¼ geometric mean; Min ¼ minimum; Max ¼ maximum; AUCτ ¼ AUC from time 0 through 1 dosing interval; Dapa ¼ dapagliflozin; Met ¼ metformin; XR ¼ extended release; IC ¼ individual component; FDC ¼ fixed-dose combination. * AUC0–1 and t1/2 data of 1 subject were excluded from the summary of treatment due to AUC extrapolated 420%.
Clinical Therapeutics
8 Table II. Plasma pharmacokinetic parameters
M. Chang et al.
Table III. Bioequivalence and food effect Ratio (90% CI) of Adjusted GMs Variable Dapagliflozin Dapa 5 mg/Met XR 500 mg (study 1) FDC/IC, fed 1.012 FDC/IC, fed (potency corrected)* 1.027 FDC fed/fasted 0.659 Dapa 10 mg/Met XR 1000 mg (study 2) FDC/IC, fed 0.937 0.927 FDC/IC, fed (potency corrected)† FDC fed/fasted 0.656 Metformin Dapa 5 mg/Met XR 500 mg (study 1) FDC/IC, fed 0.975 0.957 FDC/IC, fed (potency corrected)‡ FDC fed/fasted 1.037 Dapa 10 mg/Met XR 1000 mg (study 2) FDC/IC, fed 1.001 0.983 FDC/IC, fed (potency corrected)§ FDC fed/fasted 1.016
AUC0–T
AUC0–1
(0.944–1.086) (0.957–1.101) (0.614–0.706)
1.018 (0.990–1.047) 1.032 (1.004–1.062) 0.905 (0.880–0.931)
1.019 (0.988–1.050) 1.033 (1.002–1.065) 0.907 (0.884–0.931)
(0.868–1.010) (0.860–1.000) (0.605–0.711)
0.972 (0.950–0.995) 0.963 (0.940–0.985) 0.921 (0.900–0.941)
0.971 (0.948–0.995) 0.961 (0.938–0.985) 0.922 (0.902–0.942)
(0.920–1.032) (0.903–1.014) (0.949–1.133)
0.981 (0.928–1.038) 0.964 (0.911–1.019) 1.012 (0.948–1.080)
0.985 (0.930–1.042) 0.967 (0.914–1.023) 0.990 (0.926–1.059)
(0.957–1.047) (0.940–1.028) (0.926–1.114)
0.974 (0.921–1.031) 0.957 (0.905–1.012) 1.054 (0.980–1.134)
0.979 (0.927–1.034) 0.961 (0.910–1.015) 1.026 (0.959–1.099)
Cmax
GM ¼ geometric mean; Dapa ¼ dapagliflozin; Met ¼ metformin; XR ¼ extended release; FDC ¼ fixed-dose combination; IC ¼ individual component. Potency-corrected results obtained by multiplying the adjusted GM ratio and 90% CI by the correction factor (correction factor ¼ measured content of reference treatment/measured content of test treatment). * Correction factor 4.98/4.91 ¼ 1.014. † Correction factor 9.9/10 ¼ 0.99. ‡ Correction factor 489/498 ¼ 0.982. § Correction factor 978/996 ¼ 0.982.
(0.9–1.2), indicating little or no food effect for metformin when either dose of the FDC was administered.
PK Assessment of Multiple Doses versus Single Doses in the Fed State When FDC dapagliflozin/metformin XR 5 mg/500 mg or 10 mg/1000 mg was administered as a single dose in the fed state, the GM Cmax of dapagliflozin was 46.5 and 93.7 ng/mL, respectively. After 4 days of once-daily dosing with either dose, the GM Cmax of dapagliflozin was 51.6 and 92.5 ng/mL, respectively, indicating little if any accumulation. The GM AUCτ of dapagliflozin after repeated dosing (272 ng/mL/h) was similar to the GM AUC0–1 after a single dose ] 2015
(246 ng/mL/h) of FDC dapagliflozin/metformin XR 5 mg/500 mg; the same was true with the 10 mg/1000 mg FDC (507 vs 489 ng/mL/h) (Table II). After 4 days of administration of the FDC at either dose in the fed state, the 0- to 24-hour mean plasma profile of dapagliflozin was slightly higher compared with the mean profile after single-dose administration, indicating modest accumulation with multiple dosing. After once-daily dosing with either dose of the FDC, GM trough plasma dapagliflozin concentrations increased slightly (day 2–day 5). After 4 days of once-daily administration of either dose of the FDC in the fed state, the 0- to 24-hour mean plasma profile of metformin was slightly higher compared with the mean profile after single-dose
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Clinical Therapeutics administration, with no evidence of “dose dumping” (ie, the unexpectedly rapid release of drug from an XR formulation). After once-daily dosing with either dose of the FDC in the fed state, GM trough plasma metformin concentrations increased slightly from day 2 to day 5. After 4 days of once-daily FDC dosing (dapagliflozin/metformin XR 5 mg/500 mg or 10 mg/ 1000 mg) in the fed state, Cmax and Tmax for metformin were similar to the corresponding values after single-dose administration (Table II). The GM AUCτ for metformin after repeated dosing was similar to the GM AUC0–1 after a single dose.
Safety and Tolerability Profile Generally, both FDCs were well tolerated in the fed and fasted state, as single oral doses or after oncedaily dosing for 4 days. There were no deaths, serious AEs, or clinically significant laboratory abnormalities, and vital signs and physical examination findings were normal. There were no discontinuations due to AEs. In study 1, a total of 18 subjects reported 55 AEs. Headache was the most common AE and occurred in 16.7% of subjects; the incidence was similar with all treatments but slightly higher in the fasted state. Most AEs were considered by the investigator not to be study drug related. Two moderate AEs (headache and feeling hot) occurred. In study 2, a total of 10 subjects reported 17 AEs (6 were considered related to study drug); the incidence was similar for single doses of treatments in the fed state but slightly higher for treatment in the fasted state. For all treatments, gastrointestinal AEs were the most common (13.9%); 2 subjects experienced abdominal pain. One moderate AE (urinary tract infection) was reported with FDC dapagliflozin/ metformin XR 10/1000 mg in the fed state; it resolved with antibiotic treatment (ciprofloxacin). No moderate events were documented in the other study arms.
DISCUSSION The addition of dapagliflozin to the treatment regimen for patients with T2DM who have inadequate glycemic control on metformin alone results in significant reductions in glycosylated hemoglobin, with a low risk of hypoglycemia and an adequate safety and tolerability profile.3,5–7 The results reported here establish the PK findings and bioequivalence of an FDC of dapagliflozin/metformin XR (5 mg/500 mg and 10 mg/1000 mg) to the corresponding IC in the
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fed state in healthy adults. Across-study analyses have shown that the PK values of dapagliflozin and metformin are comparable between healthy subjects and patients with T2DM with normal renal function. Thus, the findings of this study in healthy subjects may be translatable to patients with T2DM.11,12 Assessment of the impact of food on the bioavailability of dapagliflozin in FDC formulations with metformin did not identify a meaningful food effect. Because the cumulative amount of glucose excreted in the urine, and hence dapagliflozin efficacy, are dependent upon AUC and not peak concentration as determined by Cmax,13 the reduction of dapagliflozin Cmax under fed conditions (dapagliflozin 5 mg/ metformin XR 500 mg, 34.1% reduction; dapagliflozin 10 mg/metformin XR 1000 mg, 34.4% reduction) is unlikely to be clinically meaningful. Therefore, patients should be able to take the FDC of dapagliflozin/metformin without regard to meals. This effect was consistent with earlier findings from Kasichayanula et al.13 Single- and multiple-dose PK findings for both dapagliflozin and metformin were similar with either dose of the FDC, and only slight accumulations of dapagliflozin and metformin were observed. This is consistent with previous findings for metformin.14 Dose dumping is an important consideration in the development of XR dosage forms. The phenomenon happens when an unintended bolus or rapid release of drug occurs from a modified-release formulation, often in association with food or coingestion of ethanol.15 This study found no evidence of dose dumping during the multiple-dose assessment period, indicating that the performance of the XR metformin component is unaffected by formulation into a once-daily FDC with dapagliflozin. In T2DM, the use of FDCs offers several advantages over the use of ICs; the convenience of oncedaily dosing and a lower daily tablet burden could potentially lead to reduced cost to the patient (1 prescription compared with 2) and improved adherence to treatment.10 An XR FDC of dapagliflozin and metformin has the potential to provide these benefits to patients with T2DM. Recently, several other antidiabetic or related therapeutic agents have been developed into FDCs, including saxagliptin/metformin XR and atorvastatin/ metformin XR.16,17 Establishing a treatment strategy that incorporates FDCs may simplify diabetes
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M. Chang et al. treatment regimens and support the management of concurrent conditions also requiring drug treatment by reducing the pill burden on patients. There were no unexpected or unusual safety or tolerability concerns with the FDC or the IC tablets in single doses administered to healthy adults, in the fed or fasting states or with the FDC in multiple doses in the fed state in either study.
CONCLUSIONS Bioequivalence of both dapagliflozin and metformin was established between the XR FDC tablets and the IC tablets with either dose when administered in the fed state and for both doses of the FDC of dapagliflozin/metformin between the fed and fasted state. The PK values of dapagliflozin or metformin were not changed at either dose of the FDC by repeated oncedaily dosing over 4 days, and there was no evidence of dose dumping during the dosing period. There were no apparent safety or tolerability concerns with the XR FDC tablets at either dose when administered to healthy subjects in the fed or fasted state. These results support the validity of the FDC of dapagliflozin/ metformin for the treatment of T2DM, as bioequivalence was established and the PK properties of dapagliflozin and metformin were not changed by multiple dosing over 4 days.
ACKNOWLEDGMENTS The study was sponsored by Bristol-Myers Squibb and AstraZeneca. The authors thank Sreeneeranj Kasichayanula for his contributions to this study. Medical writing assistance was provided by Ray Ashton and Lisa Bergstrom of PPSI (a PAREXEL company), funded by AstraZeneca. Each author made a material contribution to the manuscript through development of content and review during drafting of the manuscript. All authors provided approval of the final article.
CONFLICTS OF INTEREST Mr. Chang, Dr. Liu, Dr. LaCreta, Dr. Griffen, Ms. Lubin, Ms. Quamina‐Edghill, and Dr. Boulton are stockholders and/or employees of Bristol-Myers Squibb. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
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REFERENCES 1. Glucophage [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2009. 2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577–1596. 3. Katsiki N, Papanas N, Mikhailidis DP. Dapagliflozin: more than just another oral glucose-lowering agent? Expert Opin Investig Drugs. 2010;19:1581–1589. 4. Meng W, Ellsworth BA, Nirschl AA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008;51:1145–1149. 5. List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–657. 6. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–2233. 7. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–2224. 8. Wilding JP, Norwood P, T'joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32: 1656–1662. 9. Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–1031. 10. Bell DS. Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. Diabetes Obes Metab. 2013;15:291–300. 11. Kasichayanula S, Liu X, Lacreta F, et al. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014;53:17–27. 12. Duong JK, Kumar SS, Kirkpatrick CM, et al. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clin Pharmacokinet. 2013; 52:373–384. 13. Kasichayanula S, Liu X, Zhang W, et al. Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects. Diabetes Obes Metab. 2011;13:770–773.
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Clinical Therapeutics 14. Timmins P, Donahue S, Meeker J, Marathe P. Steady-state pharmacokinetics of a novel extendedrelease metformin formulation. Clin Pharmacokinet. 2005;44:721– 729. 15. Hendeles L, Weinberger M. Selection of a slow-release theophylline product. J Allergy Clin Immunol. 1986;78:743–751. 16. Boulton DW, Smith CH, Li L, et al. Bioequivalence of saxagliptin/metformin extended-release (XR) fixeddose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects. Clin Drug Investig. 2011;31:619–630. 17. Kandhwal K, Dey S, Nazarudheen S, et al. Pharmacokinetics of a fixeddose combination of atorvastatin and metformin extended release versus concurrent administration of individual formulations: a randomized, open-label, two-treatment, two-period, two-sequence, singledose, crossover, bioequivalence study. Clin Drug Investig. 2011;31: 853–863.
Address correspondence to: David W. Boulton, PhD, PO Box 4000, Bristol‐Myers Squibb, Princeton, NJ 08543‐4000. E-mail: [email protected]
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