Summary Report of Bioequivalence Study Date of Report : May 2023

Dapagliflozin 200 mg Page : 1 of 10

BIOEQUIVALENCE STUDY OF DAPAGLIFLOZIN 10 MG FILMCOATED TABLET

PRODUCED BY PT DEXA MEDICA IN COMPARISON WITH THE COMPARATOR
DRUG (FORXIGA® 10 MG FILM-COATED TABLET, MANUFACTURED BY
ASTRAZENECA PHARMACEUTICALS LP, USA FOR ASTRAZENECA
PHARMACEUTICALS CO. LTD., CHINA IMPORTED BY PT ASTRAZENECA
INDONESIA, INDONESIA)

BE. 754/EQL/2022

AUTHOR:
1. Danang Agung Yunaidi, MD
2. Yantirta Indra Kurniawan, Chem
3. Natalia Denda Wijaya, MD
4. Vicky Achmad Ginanjar, Pharm, B.Pharm
5. Ismail Dwi Saputro, Chem
6. Deny Kurniawan
7. Ima Aisyah Rahma, Pharm, B. Pharm
8. Hening Puspa Seruni, Pharm, B. Pharm
9. Purnama Dewi Yuli Astuti, Pharm, B.Pharm

INSTITUTION:
PT Equilab International
Jl. RS Fatmawati Persil 33
Jakarta 12430 – Indonesia

CORRESPONDENCE:
PT Equilab International
Jl. RS Fatmawati Persil 33
Jakarta 12430 – Indonesia
Phone: +6221 7695513, 7515932
Fax: +6221 7509668
Website: www.equilab-int.com

Jakarta, May 2023

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BIOEQUIVALENCE STUDY OF DAPAGLIFLOZIN 10 MG FILMCOATED TABLET

PRODUCED BY PT DEXA MEDICA IN COMPARISON WITH THE COMPARATOR
DRUG (FORXIGA® 10 MG FILM-COATED TABLET, MANUFACTURED BY
ASTRAZENECA PHARMACEUTICALS LP, USA FOR ASTRAZENECA
PHARMACEUTICALS CO. LTD., CHINA IMPORTED BY PT ASTRAZENECA
INDONESIA, INDONESIA)

Abstract

The present study was to compare the bioavailability of dapagliflozin 10 mg film-coated

tablet (produced by PT Dexa Medica, Indonesia) as the test drug was equivalent to that
of the comparator drug (Forxiga® 10 mg Film-Coated Tablet, manufactured by
AstraZeneca Pharmaceuticals LP, USA for AstraZeneca Pharmaceuticals Co. Ltd.,
China imported by PT AstraZeneca Indonesia, Indonesia).

This was an open-label, randomized, single-dose, two-period, two-sequence, two-way

crossover study under fasting conditions which included 24 healthy adult male and
female subjects. Of 24 subjects, two subjects dropped out from the study due to personal
reason in period 2. Hence, only 22 subjects completed and were analysed for
bioequivalence calculation of dapagliflozin.

The participating subjects were required to have 8 hours overnight fast and in the next
morning (first day of period) were given orally the test drug (dapagliflozin 10 mg film-
coated tablet produced by PT Dexa Medica) or the comparator drug (Forxiga® 10 mg
Film-Coated Tablet, manufactured by AstraZeneca Pharmaceuticals LP, USA for
AstraZeneca Pharmaceuticals Co. Ltd., China imported by PT AstraZeneca Indonesia,
Indonesia) with a total 240 mL of a 20% glucose solution in water.

Blood samples were drawn before taking the drug (control), and at 0.25, 0.50, 0.75, 1.00,
1.25, 1.50, 1.75, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 24.00, 36.00 and 48.00 hours after
drug administration. These blood samples were used to investigate the pharmacokinetic
parameters of dapagliflozin following single dose administration. This study consisted of
two periods, each for 48 hours interspaced by wash-out period for 5 days between
doses. The plasma concentrations of dapagliflozin were determined by using a validated
ultra-performance liquid chromatography with tandem mass spectroscopy detection
(UPLC-MS/MS).

There was no adverse event reported during this bioequivalence study. There was no
concomitant medication used during this bioequivalence study.

The geometric mean ratios (90% confidence intervals) of the test drug/comparator drug
were 99.21% (96.47 – 102.04%) for AUC0-t and 100.89% (89.72 – 113.46%) for Cmax,
intra-subject coefficient of variance (%ISCV) for the Cmax was 22.87%. The 90%
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confidence intervals of the test/comparator ratios for AUC0-t and Cmax of dapagliflozin
were within the acceptance range for bioequivalence (80.00 – 125.00%).

It was concluded that the dapagliflozin 10 mg film-coated tablet produced by PT Dexa

Medica was bioequivalent to the comparator drug (Forxiga® 10 mg Film-Coated Tablet,
manufactured by AstraZeneca Pharmaceuticals LP, USA for AstraZeneca
Pharmaceuticals Co. Ltd., China imported by PT AstraZeneca Indonesia, Indonesia) in
healthy subjects. All subjects tolerated both the test drug and comparator drug.
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Introduction

Bioavailability and bioequivalence of drug products have emerged as critical issues in

pharmacy and medicines during the last three decades. Bioavailability is a
pharmacokinetic term that describes the rate and extent to which the drug ingredient is
absorbed from a drug product and becomes available in the systemic circulation. The
area under the concentration versus time curve (AUC) serves as the extent of
absorption, the time to reach the peak concentration (tmax) reflects the rate of absorption,
while the peak concentration (Cmax) reflects both the extent and the rate of absorption.

The purpose of bioequivalence study is to show whether the bioavailability of the

formulations under investigation are similar. Based on that conclusion, one may
subsequently claim that the therapeutic quality of these formulations is essentially the
same. The latter means that both the beneficial and side effects are the same and hence
the formulations are interchangeable. (1)

This bioequivalence study was conducted in accordance with the Guideline on the
Investigation of Bioequivalence, EMA, London, 2010; ASEAN Guideline for the Conduct
of Bioequivalence Study, Lao PDR, 2015; and Indonesian guidelines, Tata Laksana Uji
Bioekivalensi, Badan Pengawas Obat dan Makanan (BPOM), Jakarta, 2022. (1-3)

Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-

ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate
(1:1:1). The empirical formula is C21H25ClO6•C3H8O2•H2O and the molecular weight is
502.98. (4) The chemical structure of dapagliflozin is:

Figure 1. Chemical structure of dapagliflozin

Dapagliflozin is a potent, competitive, reversible, highly selective, and orally active

inhibitor of the human sodium-glucose co-transporter 2 (SGLT2), the major transporter
responsible for the renal glucose reabsorption. It improves glycaemic control in patients
with T2DM by reducing renal glucose reabsorption leading to urinary glucose excretion
(glucuresis). SGLT2 is almost exclusively expressed in the kidney minimising the risk of
off-target (i.e., non-kidney) effects. (5)

Dapagliflozin is indicated in adults and children aged above 10 years for the treatment of
insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise as
monotherapy when metformin is considered inappropriate due to intolerance and
addition to other medicinal products for the treatment of type 2 diabetes. Dapagliflozin is
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also indicated for the treatment of symptomatic chronic heart failure with reduced
ejection fraction and for the treatment of chronic kidney disease. (6)

The recommended starting dose is 10 mg once daily for monotherapy and add-on
combination therapy with other glucose lowering drugs including insulin. Dapagliflozin
can be taken orally one daily at any time of a day taken with or without food. When
dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a
sulphonyl urea, a lower dose of insulin or insulin secretagogue may be considered to
reduce the risk of hypoglycaemia. In patients with heart failure and chronic kidney
disease, the recommended dose is 10 mg once daily. In patients with severe hepatic
impairment a starting dose of 5 mg is recommended. (6)

Dapagliflozin was rapidly and well absorbed after oral administration. Maximum
dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after
administration in the fasted state. The absolute oral bioavailability of dapagliflozin
following the administration of a 10 mg dose is 78%. Administration with a high-fat meal
decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1
hour but did not alter AUC as compared with the fasted state. Hence, dapagliflozin can
be administered with or without food. (6)

Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in
various disease states (e.g., renal, or hepatic impairment). Dapagliflozin is extensively
metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive
metabolite. Dapagliflozin and related metabolites are primarily eliminated via urinary
excretion with less than 2% as unchanged dapagliflozin. Dapagliflozin exposure
increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500
mg and its pharmacokinetics did not change with time upon repeated daily dosing for up
to 24 weeks. (6)

Adverse reactions which may occurred during dapagliflozin administrations are

hypoglycaemia, dehydration, hypotension, vulvovaginitis, balanitis and related genital
infections, urinary tract infection, dizziness, rash, back pain, dysuria, polyuria,
dyslipidaemia, haematocrit increased, fungal infection, volume depletion, thirst,
constipation, dry mouth, nocturia, pruritus genital, blood creatinine increased, blood urea
increased, diabetic ketoacidosis and angioedema. (6)

The objective of this study was to find out whether the bioavailability of dapagliflozin 10
mg film-coated tablet produced by PT Dexa Medica, Indonesia is equivalent to the
comparator drug (Forxiga® 10 mg Film-Coated Tablet, manufactured by AstraZeneca
Pharmaceuticals LP, USA for AstraZeneca Pharmaceuticals Co. Ltd., China imported by
PT AstraZeneca Indonesia, Indonesia) when administered under fasting condition in
healthy subjects.
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Methods
Study design

This was an open-label, randomized, single-dose, two-period, two-sequence, two-way

crossover study under fasting conditions which included 24 healthy adult male and
female subjects, with at least 5 days washout period. The study was a bioequivalence
study of dapagliflozin 10 mg film- coated tablet (produced by PT Dexa Medica,
Indonesia) as the test drug versus Forxiga® 10 mg Film-Coated Tablet (manufactured by
AstraZeneca Pharmaceuticals LP, USA for AstraZeneca Pharmaceuticals Co. Ltd.,
China imported by PT AstraZeneca Indonesia, Indonesia) as the comparator drug when
administered under fasting condition in healthy male and female subjects.

This study was carried out in accordance with the Declaration of Helsinki and its
amendment and to the relevant Good Clinical Practice (GCP) standards and in
agreement with the local Ethics Committee. The final version of the protocol together the
written informed consent statement had been reviewed and approved by the The
Independent Ethics Committee of the Medical Faculty, University of Indonesia prior to
the study conduct. Written informed consent was obtained from each volunteer prior to
their participation.

Subjects underwent a medical examination within 21 days prior to their first dosing day.
This included assessment of vital signs (blood pressure, pulse rate, respiratory rate, and
body temperature), physical examination, body mass index (body weight and body
height), 12-lead ECG, and clinical laboratory tests (liver function, renal function,
hematology, urinalysis, immunology test, and blood glucose). Pregnancy test was
performed for female subjects at Screening and on each Study Check-In.

The criteria were set to ensure a subject population without accompanying diseases
interfering with the conduct and scientific evaluation of the study. Healthy male and
female subjects with absence of significant disease or clinically significant abnormal
laboratory values on laboratory evaluation, medical history or physical examination
during the screening between 18 and 55 years of age, preferably non-smokers or smoke
less than 10 cigarettes per day, body weight within normal range (BMI = 18 – 25 kg/m2),
blood pressure and pulse rate within normal range, and had signed the informed
consent, were recruited to participate in this study.

History of allergy or hypersensitivity to dapagliflozin or allied drugs. Pregnant or lactating

female, any major illness in the past 90 days or clinically significant ongoing chronic
medical illness, liver dysfunction, clinically significant hematology abnormalities, renal
insufficiency, past history of anaphylaxis or angioedema, any surgical or medical
condition (present or history) which might significantly alter the absorption, distribution,
metabolism or excretion of the study drug, positive test results for HBsAg, anti-HCV,
and/or anti-HIV and have Positive result for COVID-19 antigen rapid test were excluded.

In the morning of the dosing day, a 5 mL pre-dose pharmacokinetic blood sample was
taken. Afterwards, the subjects were administered with either one test drug or one
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comparator drugs. The study drugs were given with a total 240 mL of a 20% glucose
solution in water and swallowed whole without chewing.

A 5 mL blood sample was drawn by venipuncture before taking the drug (control), and 5
mL each at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00,
24.00, 36.00 and 48.00 hours after drug administration. This study consisted of two
periods, each for 48 hours interspaced by wash-out period for 5 days between doses.
The blood sample.

A 5 mL blood sample was drawn by venipuncture before taking the drug (control), and 5
mL each at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00,
24.00, 36.00 and 48.00 hours after drug administration. This study consisted of two
periods, each for 48 hours interspaced by wash-out period for 5 days between doses.
The blood samples at each time point from all subjects collected in K3EDTA vacuum
tubes. During the study, each complaint or adverse event experienced by study subjects
was recorded and handled by the responsible medical doctor with the best possible care
and treatment.

Analytical Procedures

The samples were centrifuged at 1538 ± 10 g (corresponding to 4000 rpm with radius of
rotor = 86 mm and 3140 rpm with radius of rotor = 14 cm) for 15 minutes to separate
plasma at room temperature, and then plasma was transferred to a clean tube and
stored at -20°C ± 5°C until assayed. The samples were analyzed on LC-MS/MS system
consisting of LC Waters Acquity UPLC HClass and MS/MS detector Waters XEVO TQS
Micro (ANL-TQSM 1). The signal was recorded by software MassLynx V4.1, SCN 945
(Waters, USA).

Statistical Analysis

Phoenix® WinNonlin® Version 8.3 (Certara L.P., St. Louis, MO, USA) was used to
perform the statistical analyses of AUC0-t and Cmax using analysis of variance
(ANOVA) after transformation of the data to their logarithmic (ln) values.

The tmax was analyzed non-parametrically on the original data using Wilcoxon matched-
pairs signed-rank test. The t½ difference was analyzed using Student’s paired-t test or
Wilcoxon matched-pairs test depending on whether the differences of the paired data
were distributed normally or not.

The criteria for bioequivalence were that the 90% confidence interval of the
Test/Reference geometric means within 80.00-125.00%, 80% power and 0.05 alpha, for
AUC0-t and Cmax.

This acceptance criteria are according to the Indonesian guidelines, Tata Laksana Uji
Bioekivalensi, Badan Pengawas Obat dan Makanan (BPOM), Jakarta, 2022; ASEAN
Guideline for the Conduct of Bioequivalence Study, Lao PDR, 2015; and Guideline on
the Investigation of Bioequivalence, EMA, London, 2010.
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Results

Twenty-four (24) subjects were enrolled in the study. Of 24 subjects, two subjects (S11
and S22) did not attend period 2 due to personal matters. Hence, only 22 subjects
completed the study and were analyzed for pharmacokinetic and bioequivalence
calculation of dapagliflozin.

The summary of pharmacokinetic parameters of dapagliflozin after single Dose

Administration of 1 x Dapagliflozin 10 mg Film-Coated Tablet (Produced by PT Dexa
Medica, Indonesia) as The Test Drug (T) and the reference drug ® are shown in Table 1
(page 8) and Figure 2 (page 9).

Table 1. Summary of pharmacokinetic parameters of dapagliflozin after a single dose

administration of 1 x dapagliflozin 10 mg film-coated tablet (produced by PT Dexa Medica,
Indonesia) as the test drug and 1 x Forxiga® 10 mg film-coated tablet (manufactured by
Astrazeneca Pharmaceuticals LP, USA for Astrazeneca Pharmaceuticals Co. Ltd., China
imported by PT Astrazeneca Indonesia, Indonesia) as the comparator drug (n= 22
subjects).
Arithmetic Mean (SD)
Parameter
Test drug Comparator drug
Cmax (ng.mL-1) 83.07 (30.34) 80.29 (17.92)
-1
AUC0-t (ng.h.mL ) 601.72 (174.46) 606.64 (176.24)
-1
AUC0-inf (ng.h.mL ) 620.87 (180.38) 626.15 (182.05)
t½ (h) 10.50 (2.64) 10.53 (2.69)
tmax (h)* 2.00 (0.50 – 8.00) 2.00 (1.00 – 6.00)
*median (range)

Statistical calculations for AUC0-t and Cmax were based on the ln-transformed data and
the calculated 90% confidence intervals of test/reference geometric means ratios. These
ratios are presented below table:

Table 2. Statistical Calculations for AUC0-t and Cmax of dapagliflozin after a single dose
administration of 1 x dapagliflozin 10 mg film-coated tablet (produced by PT Dexa Medica,
Indonesia) as the test drug and 1 x Forxiga® 10 mg film-coated tablet (manufactured by
Astrazeneca Pharmaceuticals LP, USA for Astrazeneca Pharmaceuticals Co. Ltd., China
imported by PT Astrazeneca Indonesia, Indonesia) as the comparator drug (n= 22
subjects).

% Ratio of 90% Confidence Interval

(T/R) Statistical
Parameter Geometric ISCV (%) Conclusion
Power (%)
Means (T/R) Lower Limit Upper Limit
Cmax 100.89 89.72 113.46 22.87 93.20
Bioequivalent*
AUC0-t 99.21 96.47 102.04 5.41 100.00
*Bioequivalence criteria: 90% Confidence Interval of AUC0-t and Cmax was within range of 80.00 - 125.00%.
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Vertical bars indicate standard deviation.

Figure 2. Mean plasma concentration-time profiles of Dapagliflozin in human subjects after

a single dose administration of 1 x dapagliflozin 10 mg film-coated tablet (produced by PT
Dexa Medica, Indonesia) as the test drug and 1 x Forxiga® 10 mg film-coated tablet
(manufactured by Astrazeneca Pharmaceuticals LP, USA for Astrazeneca Pharmaceuticals
Co. Ltd., China imported by PT Astrazeneca Indonesia, Indonesia) as the comparator drug
(n= 22 subjects).

The half-life values of the test and the comparator drug were calculated utilizing
Student’s paired t-test and the result were not significantly different, demonstrating a
comparable rate of drug elimination from the body. The tmax values of the two drugs (test
and comparator drugs) were calculated using Wilcoxon matched-pairs test on the
original data and the result were not significantly different, demonstrating that the
absorption of the test drug was expected to be similar with the comparator drug.

There was no adverse event reported during this bioequivalence study.

Conclusion

Based on the results of the single dose study above, it was concluded that the
dapagliflozin 10 mg film-coated tablet produced by PT Dexa Medica are bioequivalent to
the Forxiga® 10 mg Film-Coated Tablet, manufactured by AstraZeneca Pharmaceuticals
LP, USA for AstraZeneca Pharmaceuticals Co. Ltd., China imported by PT AstraZeneca
Indonesia, Indonesia in healthy subjects.
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References

1. Badan Pengawas Obat dan Makanan. Peraturan Badan Pengawas Obat dan
Makanan Republik Indonesia Nomor 11 Tahun 2022 Tentang Tata Laksana Uji
Bioekivalensi. Jakarta: BPOM; 2022.
2. European Medicines Agency. Guideline on the Investigation of Bioequivalence.
London: European Medicines Agency; 2010.
3. ASEAN. ASEAN Guideline for the Conduct of Bioequivalence Study. Lao PDR:
ASEAN; 2015.
4. RxList. Farxiga (Dapagliflozin): drug description, indication & dosage, side effect &
drug interactions, warning & precautions, overdosage & contraindications, clinical
pharmacology [Internet]. 2023 [cited 2023 June 26]. Available from URL:
https://www.rxlist.com/farxiga-drug.htm
5. European Medicines Agency. Assessment report: Forxiga (Dapagliflozin). London:
2012.
6. European Medicines Agency. Summary of Product Characteristics: Forxiga 5 and 10
mg Film-Coated Tablets. London: 2022.