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Bioequivalence of Sitagliptin/Metformin Fixed-Dose Combination Tablets and
Concomitant Administration of Sitagliptin and Metformin in Healthy Adult
Subjects
Article in Clinical Drug Investigation · December 2010
DOI: 10.2165/11538410-000000000-00000 · Source: PubMed
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ORIGINAL RESEARCH ARTICLE
Clin Drug Investig 2010; 30 (12): 855-866
1173-2563/10/0012-0855/$49.95/0
ª 2010 Adis Data Information BV. All rights reserved.
Bioequivalence of Sitagliptin/Metformin
Fixed-Dose Combination Tablets and
Concomitant Administration of Sitagliptin
and Metformin in Healthy Adult Subjects
A Randomized, Open-Label, Crossover Study
Elizabeth M. Migoya,1 Jutta L. Miller,1 Maria Gutierrez,2 Wei Zheng,1
Amy O. Johnson-Levonas,1 Qi Liu,1 Catherine Z. Matthews,1 John A. Wagner1
and Keith M. Gottesdiener1
1 Merck & Co., Inc., Rahway, New Jersey, USA
2 Comprehensive Neuroscience, Inc., Miramar, Florida, USA
Abstract
Background: Treatment with an oral antihyperglycaemic agent administered
as monotherapy is often unsuccessful at achieving or maintaining glycaemic
control in patients with type 2 diabetes mellitus. The combined use of sitagliptin and metformin is an effective treatment for type 2 diabetes mellitus, consistent with the complementary mechanisms of action by which these two
agents improve glucose control.
Objectives: To establish bioequivalence between sitagliptin/metformin fixeddose combination (FDC) tablets (Janumet) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets.
Methods: This was an randomized, open-label, two-part, two-period crossover study, which included a total of 48 healthy subjects, 24 subjects per part
(parts I and II). Within each part, subjects were assigned to receive treatments
in random order; treatment periods were separated by a washout interval of
at least 7 days. Eligible study participants included healthy, non-smoking
(within previous 6 months), male and female subjects aged between 18 and
45 years with a body mass index £32 kg/m2. Part I consisted of treatments A (coadministration of sitagliptin 50 mg and metformin 500 mg) and B (sitagliptin/
metformin 50 mg/500 mg FDC tablet); part II consisted of treatments C
(co-administration of sitagliptin 50 mg and metformin 1000 mg) and D (sitagliptin 50 mg/metformin 1000 mg FDC tablet). Blood samples were collected
pre-dose and up to 72 hours post-dose in each treatment period for determination of plasma sitagliptin and metformin concentrations and calculation
of the respective pharmacokinetic parameters.
The area under the plasma concentration-time curve from time zero to
infinity (AUC¥) and the maximum plasma concentration (Cmax) for both
Migoya et al.
856
sitagliptin and metformin were designated as the primary and secondary
study endpoints, respectively, and analysed using an ANOVA model after
logarithmic transformation of the data. Bioequivalence was established if the
90% confidence intervals (CIs) for the geometric mean ratios (GMRs; FDC
tablet/co-administration) of the AUC¥ and Cmax for both sitagliptin and
metformin fell within pre-specified bounds of (0.80, 1.25).
Results: The GMRs (90% CI) for the AUC¥ of sitagliptin 50 mg and metformin 500 mg were 0.98 (0.96, 1.00) and 1.0 (0.95, 1.04), respectively, and for
Cmax of sitagliptin and metformin were 1.00 (0.94, 1.06) and 1.00 (0.94, 1.06),
respectively. The GMRs (90% CI) for the AUC¥ of sitagliptin 50 mg and
metformin 1000 mg (part II) were 0.97 (0.95, 0.99) and 1.00 (0.94, 1.07), respectively, and for the Cmax of sitagliptin and metformin were 0.94 (0.88,
1.01) and 1.01 (0.93, 1.10), respectively. In both part I and part II, the 90%
CIs of the GMRs of the AUC¥ and Cmax for both sitagliptin and metformin
all fell within the pre-specified bioequivalence bounds of (0.80, 1.25). Administration of single doses of sitagliptin/metformin 50 mg/500 mg (part I) and
50 mg/1000 mg FDC tablets (part II) and co-administration of corresponding
doses of sitagliptin and metformin as individual tablets were generally well
tolerated.
Conclusion: The sitagliptin/metformin 50 mg/500 mg and 50 mg/1000 mg FDC
tablets are bioequivalent to co-administration of corresponding doses of sitagliptin and metformin as individual tablets and support bioequivalence to
the sitagliptin/metformin 50 mg/850 mg tablet strength. These results indicate
that the safety and efficacy profile of co-administration of sitagliptin and
metformin can be extended to the sitagliptin/metformin FDC tablets.
Introduction
Type 2 diabetes mellitus is a chronic and progressive disease arising from a complex pathophysiology involving insulin resistance, reduced
insulin secretion and increased hepatic glucose
output.[1] Monotherapy with metformin, a biguanide agent that primarily acts to lower hepatic
glucose output,[2,3] is the most widely prescribed
first-line oral antihyperglycaemic agent. As with
all oral antihyperglycaemic agents, monotherapy
with metformin is often unsuccessful at achieving
or maintaining adequate glycaemic control.[4] For
this reason, combination therapy with one or more
oral antihyperglycaemic agents is frequently required to effectively manage the treatment of
patients with type 2 diabetes.
Sitagliptin is a potent and highly selective dipeptidyl peptidase IV (DPP-4) inhibitor approved
ª 2010 Adis Data Information BV. All rights reserved.
in many countries for the treatment of patients
with type 2 diabetes.[5] The DPP-4 enzyme is responsible for the degradation of the active forms
of the incretin hormones glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic
peptide (GIP) to inactive peptides.[6,7] GLP-1 and
GIP are released by enteroendocrine cells (L and
K cells, respectively) into the systemic circulation
in response to a meal. Both hormones enhance
glucose-dependent insulin secretion from pancreatic b-cells, and GLP-1 is also associated with
a reduction in glucagon concentrations. Treatment with sitagliptin 100 mg/day increases plasma concentrations of active incretin hormones by
2- to 3-fold, leading to a reduction in fasting and
postprandial glucose concentrations.[8-15]
The combined use of sitagliptin and metformin is an effective treatment for type 2 diabetes,
consistent with the mechanisms of action by
Clin Drug Investig 2010; 30 (12)
Bioequivalence of Sitagliptin/Metformin
which sitagliptin and metformin improve glucose
control (i.e. sitagliptin enhances insulin secretion,
metformin reduces insulin resistance, and both
agents reduce hepatic glucose production).[13,14,16-21]
A phase III factorial design study conducted in
patients with type 2 diabetes demonstrated additive effects of initial combination therapy with
sitagliptin 100 mg/day and metformin 1000 mg/day
or 2000 mg/day (administered as sitagliptin 50 mg +
metformin 500 mg or 1000 mg twice daily [bid],
respectively) relative to either monotherapy alone
with mean placebo-adjusted changes from baseline in glycosylated haemoglobin (HbA1c) of -1.6%
and -2.1% (mean baseline HbA1c = 8.8%), respectively.[13] These effects were durable, and the combination was well tolerated for up to 54 weeks of
treatment.[21]
The fixed-dose combination (FDC) tablet consisting of sitagliptin 50 mg and metformin 500 mg,
850 mg or 1000 mg (Janumet; Merck & Co., Inc.,
Whitehouse Station, NJ, USA), administered as
sitagliptin 50 mg/metformin 500 mg bid, sitagliptin
50 mg/metformin 850 mg bid or sitagliptin 50 mg/
metformin 1000 mg bid, has been approved for
use in many countries for the treatment of patients with type 2 diabetes.[21] The objective of this
study was to establish bioequivalence between the
final market image sitagliptin/metformin FDC tablets and co-administration of corresponding
doses of sitagliptin and metformin as individual
tablets (sitagliptin + metformin) at the lowest and
highest tablet strengths of Janumet in healthy,
normoglycaemic, adult subjects.
Patients and Methods
Study Population
Eligible study participants included healthy,
non-smoking (within the previous 6 months),
male and female subjects aged 18–45 years with a
body mass index £32 kg/m2. Subjects were not
permitted to take prescription or non-prescription
medication for the duration of the study. Subjects
also agreed to restrict their consumption of fruit
juices, alcohol and caffeine to avoid the possible
confounding effects of these agents on the pharmacokinetics of the study treatments. Premenoª 2010 Adis Data Information BV. All rights reserved.
857
pausal women were allowed to participate in the
study if they had negative serum pregnancy test
results prior to administration of study drug in
each treatment period of the study and if they agreed
to use an appropriate double-barrier method of
contraception, or were surgically sterile.
Key exclusion criteria were: pregnant or nursing females; actual or estimated (based on the
Cockcroft-Gault equation) creatinine clearance
of approximately £80 mL/min; use of prescription
or non-prescription drugs (including herbal remedies) on a regular basis that could not be discontinued for the duration of the study beginning
2 weeks prior to the initial dose of study drug and
throughout the study; prior history of stroke,
neurological disorder or neoplastic disease; history of multiple allergies and/or hypersensitivity
to drugs (including metformin) or food; and participation in other investigational studies within
4 weeks prior to the start of the study.
Study Design
The protocol for this study (Merck protocol [P]
048-00) was approved by the Independent Ethics
Committee and was conducted in accordance
with the guidelines established by the Declaration
of Helsinki. Each subject provided written informed consent prior to the administration of
study procedures. The study was a randomized,
open-label, two-part (parts I and II), two-period,
crossover study conducted at a single site in the
US. A total of 48 healthy subjects participated in
the study; 24 subjects were each assigned to either
part I or part II of the study (figure 1). Each part
of the study was a crossover design consisting of
two single-dose treatment periods separated by a
washout interval of at least 7 days. The order in
which subjects received treatments was randomly
assigned according to a computer-generated allocation schedule within each part of the study.
Part I consisted of treatments A (co-administration of sitagliptin 50 mg and metformin 500 mg)
and B (sitagliptin 50 mg/metformin 500 mg FDC
tablet) and part II consisted of treatments C (coadministration of sitagliptin 50 mg and metformin 1000 mg) and D (sitagliptin 50 mg/metformin
1000 mg FDC tablet).
Clin Drug Investig 2010; 30 (12)
Migoya et al.
858
Treatment period 2
Treatment period 1
Sitagliptin 50 mg + metformin 500 mg
(treatment A)
Sitagliptin 50 mg + metformin 500 mg
(treatment A)
n = 12
Part I
n = 24
Sitagliptin/metformin
50 mg/500 mg
(treatment B)
Sitagliptin/metformin
50 mg/500 mg
(treatment B)
n = 12
N = 48
Sitagliptin 50 mg + metformin 1000 mg
(treatment C)
Sitagliptin 50 mg + metformin 1000 mg
(treatment C)
n = 12
Part II
n = 24
Sitagliptin/metformin
50 mg/1000 mg
(treatment D)
Sitagliptin/metformin
50 mg/1000 mg
(treatment D)
n = 12
Randomization
Pre-study
screening
Pre-dose safety
measurements
Pharmacokinetic sampling times
Pharmacokinetic sampling times
(0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10,
12, 16, 24, 32, 48 and 72 h post-dose)
(0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10,
12, 16, 24, 32, 48 and 72 h post-dose)
0
72 h
7-day
washout
0
72 h
Fig. 1. Schematic representation of the study design.
Sitagliptin tablets containing 50 mg of sitagliptin
phosphate (Januvia) were supplied by Merck &
Co., Inc. Generic metformin tablets containing
500 mg metformin hydrochloride (Apo-Metformin)
were supplied by Apotex Inc. (Weston, FL, USA).
For administration of the 1000 mg dose of metformin, two 500 mg metformin tablets were given
concomitantly. In each treatment period, subjects received study drug orally after an overnight
fast with 240 mL of water. Water consumption
was restricted 1 hour before and after study drug
administration.
Blood Sampling
In each treatment period, whole blood samples
were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3,
3.5, 4, 5, 6, 8, 10, 12, 16, 24, 32, 48 and 72 hours
post-dose. Blood samples were collected and immediately placed on ice. For determination of
plasma sitagliptin concentrations, whole blood
was collected in 4 mL evacuated tubes containing
ethylene diamine tetra-acetic acid (spray-dried) and
centrifuged at 3000 rpm for 10 minutes at 4C. For
ª 2010 Adis Data Information BV. All rights reserved.
determination of plasma metformin concentrations, whole blood was collected in 2 mL evacuated
tubes containing sodium heparin and centrifuged
at 3000 rpm for 15 minutes at 4C. Following centrifugation, plasma samples were transferred to
labeled 4.5 mL Nunc polypropylene tubes and
stored at -20C until analysis.
Analytical Methods
Plasma samples for determination of sitagliptin
concentrations were analysed by Quintiles, Inc.
(Kansas City, MO, USA) using a Cohesive Technologies high-turbulence liquid chromatography
system. Analyte and internal standards were detected by tandem mass spectrometric (MS/MS)
methods using selected reaction monitoring with
turbo-ion spray interface in the positive ion mode.
The lower limit of quantification (LLQ) for the
plasma assay was 1 ng/mL and the linear calibration range was 1–1000 ng/mL. The overall precision of the sitagliptin assay was 5% coefficient of
variation (CV). Plasma samples for determination of metformin concentrations were analysed
Clin Drug Investig 2010; 30 (12)
Bioequivalence of Sitagliptin/Metformin
by PPD, Inc. (Richmond, VA, USA) using a highperformance liquid chromatography system with
an MS/MS detection method. The LLQ for metformin was 2.0 ng/mL with a linear calibration
range of 2.0–2000 ng/mL. The overall precision of
the metformin assay was 6% CV.
Pharmacokinetic Methods
The pharmacokinetic parameters for both
sitagliptin and metformin used to establish bioequivalence were area under the plasma concentrationtime curve from time zero to infinity (AUC¥; primary
endpoint) and the maximum plasma concentration (Cmax; secondary endpoint). In addition, the
following parameters for both sitagliptin and metformin were evaluated in an exploratory manner:
time to reach Cmax (tmax), area under the plasma
concentration-time curve from time zero to time
of last measurable concentration (AUClast), apparent terminal rate constant (lz) and apparent
elimination half-life (t½).
The pharmacokinetic parameters for sitagliptin
and metformin were estimated from individual
plasma concentrations using model-independent
standard methods. The lz was estimated by regression of the terminal log-linear portion of the
plasma concentration-time profile; t½ was calculated as the quotient of ln(2) and lz. The values
for Cmax and tmax were determined from visual
examination of concentration-time data for each
subject. AUC¥ was estimated as the sum of AUC
to the last measurable concentration and the extrapolated area given by the quotient of the last
measurable concentration and lz. AUClast was
calculated using the linear (for ascending concentrations) and the log (for descending concentrations) trapezoidal methods up to the last point on
the plasma concentration-time profile where the
measured plasma concentration was greater than
the LLQ. For the primary comparisons, pharmacokinetic parameters for sitagliptin and metformin were not potency adjusted.
Statistical Analysis
An ANOVA model appropriate for a two-period,
crossover design was used to evaluate plasma
pharmacokinetics for sitagliptin and metformin
ª 2010 Adis Data Information BV. All rights reserved.
859
in both parts of the study. The ANOVA model
included factors for period (period I or II),
treatment (treatments A and B, or C and D), sequence (relating to the sequence of treatments),
and subject within sequence. A log transformation was applied to AUC¥ and Cmax; a rank
transformation was applied to tmax. The model’s
assumption of normality was tested graphically
and by using the Shapiro-Wilk statistic. Ninety
percent confidence intervals (CIs) were computed for the geometric mean ratios (GMRs; FDC
tablet/co-administration) of AUC¥ and Cmax
for sitagliptin and metformin in both parts of the
study. As recommended in the US FDA guidelines, bioequivalence was tested according to
the methodology proposed by Schuirmann.[22,23]
The ANOVA model was used to compare the
90% CIs for the GMRs of AUC¥ or Cmax with the
pre-specified comparability bounds of (0.80,
1.25). Bioequivalence was confirmed if both null
hypotheses (lack of bioequivalence) were rejected, i.e. if the 90% CIs for the GMRs of AUC¥
for sitagliptin and metformin fell within the required range, i.e. bounds of (0.8, 1.25). No statistical comparisons were made between parts I
and II of the study.
Safety and Tolerability Assessments
Data from all study participants were included
in safety and tolerability assessments. Evaluation of safety was accomplished through subjectreported adverse experiences, investigator observations and assessments, and pre-specified study
evaluations (laboratory safety tests [serum chemistry, haematology and urinalysis], ECGs and vital
sign measurements). All adverse experiences were
rated by investigators for intensity (mild, moderate,
severe) and relationship to study drug (definitely
not, probably not, possibly, probably, definitely).
Safety and tolerability were evaluated by clinical
review of all safety parameters. The numbers of
subjects with clinical adverse experiences, treatmentrelated adverse experiences (clinical and laboratory),
serious clinical adverse experiences, discontinuations due to adverse experiences, and clinically
significant laboratory abnormalities were tabulated by treatment group.
Clin Drug Investig 2010; 30 (12)
Migoya et al.
860
Results
Baseline Demographics and Subject
Accounting
The overall study population included 48 (n = 24
subjects per part) healthy, non-smoking subjects
(65% female) with a mean age of 34.7 years (range
21–45 years), a mean height of 164.8 cm (range
150–181 cm), and a mean bodyweight of 71.9 kg
(range 51–97 kg). A total of 45 (94%) Hispanic
Americans, two (4%) Blacks and one (2%) Native
American participated in the study. The subject
demographic and anthropometric characteristics
were generally well balanced between parts I and
II (table I). All 48 subjects successfully completed
the study according to the protocol.
Pharmacokinetics
Mean plasma concentration-time profiles for
sitagliptin and metformin obtained from part I
(sitagliptin/metformin 50 mg/500 mg FDC tablet and co-administration of sitagliptin 50 mg
and metformin 500 mg) and part II (sitagliptin/
metformin 50 mg/1000 mg FDC tablet and co-
Table I. Demographic and baseline anthropometric characteristics
for study subjects
Characteristic
Part I
(n = 24)
Part II
(n = 24)
Age (y)
Mean
33.6
35.1
Range
22–44
21–45
Sex (n [%])
Male
8 [33]
9 [37]
Female
16 [67]
15 [63]
Hispanic
22 [92]
23 [96]
Black
1 [4]
1 [4]
Native American
1 [4]
0
Race (n [%])
Bodyweight (kg)
Mean
78.8
71.0
Range
53–97
51–94
Mean
169.7
164.2
Range
156–181
150–179
administration of sitagliptin 50 mg and metformin
1000 mg) of the study are illustrated in figures 2
and 3, respectively. The plasma concentrations of
sitagliptin and metformin were nearly superimposable after administration of single sitagliptin/
metformin 50 mg/500 mg in part I (figure 2a and b)
or 50 mg/1000 mg FDC tablets in part II (figure 3a
and b) and co-administration of corresponding
doses of sitagliptin and metformin as individual
tablets. Summary statistics for AUC¥, Cmax, tmax
and t½ as well as the GMRs (FDC tablet/coadministration) and associated 90% CIs obtained
from parts I and II of the study are provided in
table II.
The AUC¥ and Cmax of sitagliptin and metformin were used to assess bioequivalence between
sitagliptin/metformin 50 mg/500 mg and 50 mg/
1000 mg FDC tablets and co-administration of
corresponding doses of sitagliptin and metformin
as individual tablets. After administration of the
sitagliptin/metformin 50 mg/500 mg FDC tablet
and co-administration of corresponding doses of
sitagliptin and metformin as individual tablets in
part I of the study, the GMRs (90% CI) for the
AUC¥ and Cmax of sitagliptin were 0.98 (0.96,
1.00) and 1.00 (0.94, 1.06), respectively (table II);
the GMRs (FDC tablet/co-administration; 90%
CI) for the AUC¥ and Cmax of metformin were
1.00 (0.95, 1.04) and 1.00 (0.94, 1.06), respectively.
After administration of sitagliptin/metformin
50 mg/1000 mg FDC tablet and co-administration
of corresponding doses of sitagliptin and metformin in part II of the study, the GMRs (90% CI)
for the AUC¥ and Cmax of sitagliptin were 0.97
(0.95, 0.99) and 0.94 (0.88, 1.01), respectively
(table II). The GMRs (FDC tablet/co-administration; 90% CI) for the AUC¥ and Cmax of
metformin were 1.00 (0.94, 1.07) and 1.01 (0.93,
1.10), respectively. The 90% CIs for the GMRs of
sitagliptin and metformin AUC¥ and Cmax fell
entirely within the prespecified bounds of (0.80,
1.25) required to establish bioequivalence at both
dose strengths tested (table II).
Safety and Tolerability
Height (cm)
ª 2010 Adis Data Information BV. All rights reserved.
Single oral doses of sitagliptin (50 mg) and metformin (500 [part I] or 1000 mg [part II]) as the
Clin Drug Investig 2010; 30 (12)
Bioequivalence of Sitagliptin/Metformin
861
Sitagliptin 50 mg + metformin 500 mg
co-administration
Sitagliptin/metformin
50 mg/500 mg FDC tablet
a
Sitagliptin plasma concentration (nmol/L)
450
400
350
300
250
200
150
100
50
0
0
8
16
24
32
40
48
56
64
72
8
16
24
32
40
48
56
64
72
b
1300
Metformin plasma concentration (ng/mL)
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
0
Time (h)
Fig. 2. Mean plasma concentration-time profiles of (a) sitagliptin and (b) metformin after a single dose of sitagliptin 50 mg/metformin 500 mg
fixed-dose combination (FDC) tablet and co-administration of corresponding single doses of sitagliptin 50 mg and metformin 500 mg. Error
bars represent standard errors.
sitagliptin/metformin FDC tablet or co-administration
of sitagliptin and metformin as individual tablets
were generally well tolerated in healthy adult
subjects. In part I of the study, three adverse experiences (i.e. constipation, abdominal pain and
headache) were reported for three subjects after
co-administration of sitagliptin and metformin,
ª 2010 Adis Data Information BV. All rights reserved.
and one adverse experience (i.e. abdominal pain)
was reported for one subject after administration
of the FDC tablet. In part II, two clinical adverse
experiences (i.e. ecchymotic lesions, upper respiratory infection) were reported for two subjects
after co-administration of sitagliptin and metformin, and three clinical adverse events (i.e. toothache,
Clin Drug Investig 2010; 30 (12)
Migoya et al.
862
a
Sitagliptin 50 mg + metformin 1000 mg
co-administration
Sitagliptin/metformin
50 mg/1000 mg FDC tablet
Sitagliptin plasma concentration (nmol/L)
450
400
350
300
250
200
150
100
50
0
0
8
16
24
32
40
48
56
64
72
8
16
24
32
40
48
56
64
72
b
Metformin plasma concentration (ng/mL)
2000
1800
1600
1400
1200
1000
800
600
400
200
0
0
Time (h)
Fig. 3. Mean plasma concentration-time profiles of (a) sitagliptin and (b) metformin after a single dose of sitagliptin 50 mg/metformin 1000 mg
fixed-dose combination (FDC) tablet and co-administration of corresponding single doses of sitagliptin 50 mg and metformin 1000 mg. Error
bars represent standard errors.
abdominal pain, nausea) were reported for two
subjects after administration of the FDC tablet.
All reported adverse experiences were considered
mild to moderate in intensity by the study investigator and all resolved by the end of the study.
Overall, clinical adverse experiences classified by
the study investigator as possibly, probably or
ª 2010 Adis Data Information BV. All rights reserved.
definitely drug-related occurred in a total of three
subjects (13%) in part I and none of the subjects
in part II. Of these drug-related adverse experiences, there were two reports of abdominal pain
and one report of headache; all were rated mild
in intensity. No subjects in any of the treatment
groups discontinued treatment because of an
Clin Drug Investig 2010; 30 (12)
Bioequivalence of Sitagliptin/Metformin
adverse experience, and there were no serious adverse experiences or laboratory adverse experiences reported in this study.
Discussion
Results from clinical studies show that the addition of sitagliptin provides clinically meaningful reductions in HbA1c in patients with inadequate
glycaemic control on metformin alone or metformin in dual combination therapy with either a
sulfonylurea agent or peroxisome proliferatoractivated receptor-g (PPAR-g) agonist.[24-27] Furthermore, for patients with moderate to severe
863
hyperglycaemia with inadequate control on diet
and exercise alone, initial combination therapy with
sitagliptin and metformin provided substantial
reductions in HbA1c.[13,21] An FDC tablet containing sitagliptin and metformin, two oral antihyperglycaemic agents with different but complementary
mechanisms of action, is available for the treatment
of type 2 diabetes. The objective of the current study
was to establish bioequivalence between sitagliptin/
metformin FDC tablets and co-administration of
corresponding doses of sitagliptin and metformin
as individual tablets in order to support the bridging of all relevant clinical safety and efficacy data
from prior studies of co-administration of sitagliptin
Table II. Least squares geometric meansa of the area under the plasma concentration-time curve from time zero to infinity (AUC¥), maximum
plasma drug concentration (Cmax), time to reach Cmax (tmax) and apparent elimination half-life (t½) for sitagliptin and metformin and geometric
mean ratios (GMRs)b for AUC¥ and Cmax, measured in parts I and II of the study
Sitagliptin + metformin
co-administered
Sitagliptin/metformin
FDC tablet
GMR (90% CI)
AUC¥ (mmol h/L)
4.09
4.01
0.98 (0.96, 1.00)
Cmax (nmol/L)
415
414
1.00 (0.94, 1.06)
tmax (h)c
2.50
2.75
NC
t½ (h)d
12.3
12.6
NC
Pharmacokinetic
parameter
Part I
Sitagliptin 50 mg
Metformin 500 mg
AUC¥ (mg h/mL)
7.26
7.25
1.00 (0.95, 1.04)
Cmax (ng/mL)
1180
1180
1.00 (0.94, 1.06)
tmax (h)c
2.50
2.75
NC
t½ (h)d
9.79
11.6
NC
AUC¥ (mmol h/L)
4.05
3.94
0.97 (0.95, 0.99)
Cmax (nmol/L)
423
397
0.94 (0.88, 1.01)
tmax (h)c
2.56
2.75
NC
t½ (h)d
13.1
13.7
NC
Part II
Sitagliptin 50 mg
Metformin 1000 mg
a
AUC¥ (mg h/mL)
11.9
11.9
1.00 (0.94, 1.07)
Cmax (ng/mL)
1850
1870
1.01 (0.93, 1.10)
tmax (h)c
2.48
2.13
NC
t½ (h)d
13.6
13.9
NC
Unless otherwise stated.
b
GMRs (FDC tablet/co-administration) are based on the least squares means obtained from the ANOVA model.
c
Median.
d
Harmonic mean.
FDC = fixed-dose combination; NC = not calculated.
ª 2010 Adis Data Information BV. All rights reserved.
Clin Drug Investig 2010; 30 (12)
864
and metformin to the sitagliptin/metformin FDC
tablets.[13,14,16-21]
Metformin has a well established safety and
tolerability profile that includes the common adverse experiences of nausea, vomiting and diarrhoea.[28,29] In clinical practice, treatment with
metformin is usually initiated with lower doses of
500 mg bid to reduce the frequency of gastrointestinal intolerability.[29] Since metformin is typically administered bid, administration of sitagliptin
also bid at a dose of 50 mg was selected for development of the sitagliptin/metformin FDC tablet.
A previous study demonstrated similar glycaemic efficacy, safety and tolerability profiles for a
100 mg dose of sitagliptin administered either as
50 mg bid or 100 mg once daily.[3]
To date, a substantial body of data exists demonstrating the overall favourable efficacy, safety
and tolerability profile of combination therapy
with sitagliptin and metformin in patients with
type 2 diabetes.[13,14,16-21] Co-administration of
sitagliptin and metformin produces significant
improvements in fasting and postprandial glycaemic control and measures of pancreatic b-cell function compared with metformin alone.[13,16,19] Of
note, in a mechanistic study conducted in healthy
subjects, the co-administration of sitagliptin and
metformin resulted in a more than additive effect
on active GLP-1 concentrations compared with
either treatment alone.[30] That study also demonstrated the complementary mechanisms of actions
of sitagliptin and metformin. Metformin increased
total GLP-1 levels, while sitagliptin, through its
inhibition of DPP-4 activity, prevented degradation of this peptide, resulting in approximately a
4-fold increase in active GLP-1 concentrations
when sitagliptin was used in combination with
metformin.
Results from the current study demonstrate
that the sitagliptin/metformin 50 mg/500 mg and
50 mg/1000 mg FDC tablets are bioequivalent to
co-administration of corresponding doses of sitagliptin and metformin as individual tablets. Furthermore, these results are consistent with a similarly
designed study showing bioequivalence of the
FDC tablets to the EU metformin innovator product Glucophage.[31] In the present study, for
both sitagliptin and metformin, the GMRs (FDC
ª 2010 Adis Data Information BV. All rights reserved.
Migoya et al.
tablet/co-administration) of AUC¥ and Cmax
were close to unity and the associated 90% CIs
fell entirely within the bounds of (0.80, 1.25) required to establish bioequivalence, thereby meeting the pre-specified comparability bounds associated with the study hypotheses. In the current
study, demonstration of bioequivalence between
the sitagliptin/metformin FDC tablets and coadministration of corresponding doses of sitagliptin
and metformin at the lowest (sitagliptin/metformin
50 mg/500 mg) and highest (sitagliptin/metformin
50 mg/1000 mg) tablet strengths, in conjunction
with data from dissolution testing showing similar in vitro dissolution profiles among the three
sitagliptin/metformin FDC tablet strengths (data
not shown), support bioequivalence to the intermediate (sitagliptin/metformin 50 mg/850 mg) tablet
strength. Additionally, results from a previous study
conducted in patients with type 2 diabetes demonstrated that co-administration of sitagliptin
50 mg bid with metformin 1000 mg bid did not
meaningfully alter the pharmacokinetics of either sitagliptin or metformin.[32] The lack of a
drug interaction between sitagliptin and metformin also supports extrapolation of the pharmacokinetic, efficacy and safety results from clinical
studies employing co-administration of sitagliptin
and metformin to the sitagliptin/metformin FDC
tablet.
Single doses of the sitagliptin/metformin FDC
tablet and co-administration of sitagliptin and
metformin as individual tablets were generally
well tolerated in healthy adult subjects in the current study. There were no serious adverse experiences in this study and no subjects discontinued
from the study because of an adverse experience.
Overall, clinical adverse experiences associated with
the sitagliptin/metformin FDC tablets were qualitatively similar to those seen with co-administration
of sitagliptin and metformin, and were mild to moderate, transient and self-limited in nature.
In summary, the results of the present study
indicate that the sitagliptin/metformin 50 mg/500 mg
and 50 mg/1000 mg FDC tablets are bioequivalent to co-administration of corresponding doses
of sitagliptin and metformin as individual tablets
and support bioequivalence to the sitagliptin/
metformin 50 mg/850 mg tablet strength. ThereClin Drug Investig 2010; 30 (12)
Bioequivalence of Sitagliptin/Metformin
fore, the sitagliptin/metformin FDC tablet can be
prescribed as an alternative to co-administered
sitagliptin and metformin as individual tablets.[24]
Conclusion
The results of this study demonstrate that the
sitagliptin/metformin 50 mg/500 mg and 50 mg/
1000 mg FDC tablets are bioequivalent to coadministration of corresponding doses of sitagliptin
and metformin. Demonstration of bioequivalence
in this study suggests that the sitagliptin/metformin
50 mg/500 mg and 50 mg/1000 mg FDC tablets
can be considered therapeutically equivalent and
interchangeable in clinical practice to co-administration of the corresponding doses of sitagliptin
and metformin as individual tablets, and, consequently, the efficacy and safety profile established for co-administration therapy with sitagliptin
and metformin can be extended to the sitagliptin/
metformin FDC tablets. In addition, this study supports bioequivalence at the sitagliptin/metformin
50 mg/850 mg tablet strength. Administration of
both sitagliptin/metformin FDC tablets and coadministration of sitagliptin and metformin as
individual tablets were well tolerated in healthy
adult subjects.
Acknowledgements
The funding for this study was provided by Merck Research Laboratories, Merck & Co., Inc. Elizabeth M. Migoya,
Jutta L. Miller, Wei Zheng, Amy O. Johnson-Levonas,
Qi Liu, Catherine Zhou Matthews, John A. Wagner and Keith
M. Gottesdiener are employees or former employees of Merck
& Co., Inc. and may own stock or hold stock options in the
company. Wei Zheng is currently an employee of MedImmune, Inc., Gaithersburg, MD, USA. Qi Liu is currently an
employee of the US FDA. The views expressed in this article
are those of the authors and do not reflect official policy of the
FDA. No official endorsement by the FDA is intended or
should be inferred. The authors wish to thank the clinical site
staff and subjects for their contributions to this study. In addition, Catherine Phillips and Kathleen Newcomb of Merck &
Co., Inc. provided technical support in the preparation of this
manuscript.
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Correspondence: Dr Elizabeth M. Migoya, Merck & Co.,
Inc., RY34-A544, 126 East Lincoln Avenue, P.O. Box 2000,
Rahway, NJ 07065-0900, USA.
E-mail: elizabeth_migoya@merck.com
Clin Drug Investig 2010; 30 (12)