|Year : 2022 | Volume
| Issue : 3 | Page : 235-241
Bioequivalence study of two different dapagliflozin tablet formulations in healthy adult Indian volunteers
Sanjay Kalra1, Supratik Bhattacharya2
1 Department of Endocrinology, Bharti Hospital, Karnal, Haryana, India
2 Department of Endocrinology, AMRI Hospital, Kolkata, West Bengal, India
|Date of Submission||02-Dec-2021|
|Date of Decision||09-Feb-2022|
|Date of Acceptance||22-Feb-2022|
|Date of Web Publication||12-Aug-2022|
Dr. Supratik Bhattacharya
Department of Endocrinology, AMRI Hospital, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Objective: To assess the bioequivalence of 10 mg dapagliflozin tablets compared with that of 10 mg Farxiga® (dapagliflozin) tablets of AstraZeneca Pharmaceuticals LP, USA in healthy, adult volunteers under fasting conditions. Materials and Methods: This was an open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, oral bioequivalence study. Volunteers were randomized to receive either test product or reference product of 10 mg dapagliflozin tablets under the fasting condition with a nine-day washout period. The primary pharmacokinetic (PK) parameters were maximum plasma concentration (Cmax), area under the curve (AUC) at time t (AUCt), and AUC extrapolated to infinity (AUCinf). Adverse events were assessed as safety endpoints. The bioequivalence was assessed to evaluate that the two formulations are not different from one another if the 90% confidence interval for the ratio of the geometric least square means falls completely within the predefined range of 80–125%. Results: Fifty-two healthy adult volunteers were randomized, and 47 completed the study. The mean values for Cmax, AUCt, and AUCinf were almost identical for test and reference products after administration to healthy human volunteers under fasting conditions. A total of 14 adverse events were reported by 10 volunteers during the study. All adverse events were mild to moderate in nature and did not cause study withdrawal. Conclusion: The test product dapagliflozin 10 mg was bioequivalent with the reference product in healthy, adult, human volunteers under fasting conditions. The availability of the affordable generic dapagliflozin has the potential to improve clinical outcomes in millions of patients in India because of its renoprotective, cardioprotective, and glucose-lowering effects.
Keywords: Fasting condition, pharmacokinetic, reference product, safety
|How to cite this article:|
Kalra S, Bhattacharya S. Bioequivalence study of two different dapagliflozin tablet formulations in healthy adult Indian volunteers. J Diabetol 2022;13:235-41
| Introduction|| |
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively newer class of oral antidiabetic agents. Owing to the insulin-independent action, SGLT2 inhibitors have demonstrated efficacy and safety in the management of type 2 diabetes mellitus (T2DM) with a low risk of hypoglycemia. Dapagliflozin has a mechanism of action that inhibits SGLT2 in close proximity of the renal tubule.,, It reduces the plasma glucose by impeding glucose absorption in the kidneys, thereby promoting its urinary excretion. Glucosuria, the result of the excretion of glucose in the urine, is the primary effect of dapagliflozin and results in lower hyperglycemia, body weight, and blood pressure.,,, The trials have shown that dapagliflozin not only lowers the blood glucose level but also has beneficial effects on cardiovascular and renal outcomes due to its renoprotective and cardioprotective functions.,, It reduces the risk of worsening heart failure and kidney disease-related events in patients with heart failure and chronic kidney disease (CKD), with or without T2DM.,,
Dapagliflozin is an orally administered highly soluble SGLT2 inhibitor, and it generally achieves peak plasma concentrations within 2 h with a bioavailability of 78%. The half-life of 10 mg dapagliflozin is 12.9 h. The plasma glucose and renal function are mainly responsible for changes in pharmacodynamic parameters, and a reduction in urinary glucose excretion is observed due to the lower glomerular filtration rate in healthy volunteers compared with subjects with T2DM.
India has out-of-pocket health-care expenditure, and the number of people diagnosed with diabetes is increasing at an alarming rate. Dapagliflozin has been available in India for several years, but it is not affordable to be prescribed for patients with T2DM. Currently, the use of generic products is increasing to provide therapy for patients in an affordable manner. Therefore, effort needs to be made to make the dapagliflozin tablet available at an affordable cost. From a pharmacoeconomic perspective, a recent survey-based study reported that generic dapagliflozin is an effective and cost-saving therapy compared with other SGLT-2 inhibitors in patients with T2DM with or without complications.
A bioequivalence study is an important approach to prove that the safety and efficacy of the new dapagliflozin formulation is comparable to the reference product after being administered to healthy human volunteers. Indian guidelines also indicate that bioequivalence studies are necessary for the comparison of two medicinal products containing the same active substance to prove their therapeutic equivalence to each other. A therapeutic equivalence of generic dapagliflozin provided potential benefits of compliance to the treatment and cost-effectiveness.
Moreover, it is important that the composition of generic dapagliflozin should be identical to the reference product. This will enable better clinician as well as patient acceptability and, thus, help to capture a substantial part of the pharmaceutical market. The substitution of reference products with generic products will considerably reduce the health-care cost for patients and, hence, improve compliance. The aim of this study was to assess the bioequivalence of 10 mg dapagliflozin tablets of MSN Laboratories Private Limited, India compared with that of 10 mg Farxiga® (dapagliflozin) tablets of AstraZeneca Pharmaceuticals LP, USA in healthy, adult volunteers under fasting conditions.
| Materials and Methods|| |
This was an open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, oral bioequivalence study. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization guidelines for Good Clinical Practice. The study protocol was reviewed and approved by the Institutional Ethics Committee. Written informed consent was obtained from all patients prior to their enrollment in the study.
The study population comprised adult healthy males between 18 and 45 years of age, weighing at least 50 kg; their body mass index (BMI) was between 18.5 and 24.9 kg/m2. They had a creatinine clearance >50 mL/min, were nonsmokers or ex-smokers (had stopped smoking for at least the past three months), had an acceptable medical history, had undergone a physical examination, laboratory investigations including hematology, clinical chemistry, serology, urine analysis, chest X-ray (within the past 180 days), ECG results declared within 21 days before enrollment (Laboratory values must be within normal clinical decision limits or considered by the physician/investigator to be of no clinical significance), and did not have a known allergy to dapagliflozin or any of the excipients or other related drugs.
The exclusion criteria were: volunteers with systolic blood pressure <90 mm Hg or >140 mm Hg and diastolic blood pressure <60 mm Hg or >90 mm Hg, oral temperature <95.0°F or >98.6°F, pulse rate below 60/min or above 100/min, a history of hypersensitivity or an idiosyncratic reaction to investigational drug products or any other related drugs, a history of problems of galactose intolerance/lactose intolerance, a known history of cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological, and gastrointestinal ulcer, gastrointestinal bleeding or gastrointestinal surgery, psychiatric disease or disorder, known interactions with dapagliflozin, the presence of any significant organ abnormalities, the habit of alcoholism, and tobacco chewing. Further, the consumption of xanthine-containing food or beverages (such as tea, coffee, chocolates, and cola drinks) and grapefruit/grapefruit juice/ flavonoid-containing liquids at least 48 h prior to the study check-in of each period, confirmed positive in hepatitis screening (HBsAg/HCV) or for HIV antibody, and difficulty in swallowing tablets were the additional exclusion criteria.
The test product dapagliflozin 10 mg tablet was developed by MSN Laboratories Private Limited, India, whereas the reference product Farxiga® 10 mg tablets were manufactured by AstraZeneca Pharmaceuticals LP, USA.
Volunteers who had satisfied the screening evaluations were admitted to the study center at least 11 h before drug administration. All the volunteers fasted for at least 10 h prior to drug administration. No food was allowed for at least 4 h post-dose. Standardized lunch, snacks, dinner, breakfast, lunch, snacks, and dinner were served to all the volunteers at about 4.0, 9.0, 13.0, 24.0, 28.0, 32.0, and 36.0 h post-dose, respectively. All meal contents were similar for all the volunteers throughout the study.
The study was conducted in two periods and in each period, the volunteers received either test or reference products. In both study periods, after an overnight fast of at least 10 h, a single oral dose of 10 mg tablet per volunteer was administered with about 240 mL of 20% glucose solution in water in accordance with the randomization schedule.
A single oral dose of study medication (test or reference) was administered to each volunteer in period I and period II. The treatment phases were separated by a washout period of nine days between each drug administration. In each study period, a total of 23 blood samples were drawn from pre-dose (0.00) and up to 48.00 h post-dose for each volunteer to analyze the pharmacokinetic (PK) profile of the test as well as the reference product.
Blood sample collection and processing
All blood samples were collected in prelabeled vacutainers (1 x 4 mL) containing K2EDTA as anticoagulant. Blood samples were drawn at pre-dose (0.00) and 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 7.00, 8.00, 12.00, 16.00, 24.00, 36.00, and 48.00 h post-dose in each period and collected via an indwelling catheter (when possible) or via direct venipuncture. The total blood loss for the study was 228 mL.
The pre-dose sample was collected within 1 h prior to dosing, and the post-dose samples were collected within ±2 min of the scheduled time for in-house samples; however, the actual time of sample collection was considered for PK and statistical analysis.
The plasma was separated by centrifuging the samples at 3000 RPM at 4°C for 10 min. The plasma was transferred into two prelabeled sample tubes as two aliquots (0.8 mL of plasma was transferred to each aliquot) and stored at -70°C ± 15°C till analysis.
The analysis of plasma concentrations of dapagliflozin was done by a validated LC-MS/MS method. Dapagliflozin in plasma was determined by using high-performance liquid chromatography with the tandem mass spectrometry method over a concentration range of 1.0114 to 401.13 ng/mL. The analytical method was developed and validated over a concentration range of 1.0081 to 403.15 ng/mL for dapagliflozin.
The primary PK endpoints were maximum plasma concentration (Cmax), the area under the curve (AUC) at time t (AUCt), and the total area under the curve (AUCinf). The secondary endpoints were time to reach Cmax (tmax), elimination of half-life time of dapagliflozin (t1/2), (AUC%Extrap), elimination rate constant (Kel), Kel_lower and Kel_Upper.
Safety measurements were carried out during the study, and volunteers were specifically asked about any adverse events and vital signs after admission in both periods after dosing and at the end of the study.
Areas under the concentration (AUC calculation)
AUC was calculated by using the linear trapezoidal rule.
For a given time interval (t1 – t2), the AUC can be calculated as follows:
AUC = ½ (C1 + C2) (t2 – t1)
C 1+ C2, average concentration over the time interval
t2 – t1, duration of time interval
Pharmacokinetic and statistical analysis
The PK parameters were calculated from the drug concentration versus time profile by the non-compartmental model using Phoenix® WinNonlin® Version 6.4 for dapagliflozin.
Statistical comparison of the PK parameters of two dapagliflozin formulations was carried out by using the analysis of variance (ANOVA) method using GLM of SAS® Studio 3.6 (Basic Edition), (SAS® Institute Inc. USA) for average bioequivalence to assess the bioequivalence between the test and reference product. The model included sequence, treatment, and period as fixed effects, and subject (sequence) as random effect.
ANOVA was performed in transformed PK parameters, including Cmax, AUCt, and AUCinf. The 90% confidence intervals for the ratio of test (T) and reference (R) product averages (least squares means) derived from the analysis of log (natural) transformed PK parameters must be between 80.00% and 125.00% for bioequivalence.
| Results|| |
A total of 52 volunteers were enrolled and received one of the treatment products [either test or reference product] at period I, and 48 volunteers received one of the treatment products [either test or reference product] at period II as per the randomization schedule. Forty-seven volunteers completed the clinical phase of the study [Figure 1]. Out of the five volunteers who were withdrawn from the study, three were from test product and two were from reference product. The safety issue was the most common reason for treatment discontinuation.
The mean age was 30.3 years, and all the volunteers were men [Table 1]. The Cmax, AUCt, and AUCinf of dapagliflozin (10 mg, single-dose) were comparable for test and reference product after administration to healthy human volunteers under fasting conditions. The mean value for Cmax was 114.86 (ng/mL) for the test product and 99.76 (ng/mL) for the reference product. For the test product, the mean AUCt was 586.68 (hr*ng/mL) and the mean AUCinf was 621.83 (hr*ng/mL); however, for the reference product, the mean AUCt was 575.01 hr*ng/mL and AUCinf was 618.54 hr*ng/mL [Table 2]. The concentration versus time profile was almost identical for the test and reference product after the administration of a single dose of 10 mg dapagliflozin under fasting conditions [Figure 2].
For tmax, the median value obtained was comparable between the test product (1.00 hour) and the reference product (1.50 hours). Regarding the mean t1/2, the mean value obtained for the test product was 8.52 h whereas for the reference product it was 8.85 h [Table 3].
A total of 14 adverse events were reported by 10 volunteers during the study. During period I, vomiting (7.69%) and back pain (3.85%) were reported by those taking test products whereas vomiting (7.69%), nausea (7.69%), loose motion (3.85%), itching (3.85%), and rashes (3.85%) over the forehead were adverse events reported by volunteers taking reference products. However, during period II, headache and dizziness was reported by one volunteer each from the test product group and vomiting and nausea were reported by one volunteer each from the reference product group [Table 4].
Adverse events, including nausea, back pain, itching over the forehead, rashes over the forehead, and one adverse event of vomiting, were possibly related to the study drug. All these adverse events were mild to moderate in nature and resolved over time. There were no deaths and other significant adverse events reported in this study.
| Discussion|| |
Bioequivalence studies are performed to determine the in vivo biological equivalence between two different proprietary pharmaceutical preparations in the pharmaceutical industry. Their rationale is to provide a resemblance between a generic medicine and its corresponding innovator medicine in terms of safety, quality, efficacy, dosage form, strength, and route of administration.,
The comprehensive PK and pharmacodynamics evaluation study demonstrated that dapagliflozin has high systemic exposure across a wide range of doses from 0.1 to 500 mg and its PK properties are not changed even after repeated dosing. Single-dose dapagliflozin together with diet and exercise appears to be safe and effective when given as monotherapy in patients who failed to achieve glycemic control with metformin or in combination with other glucose-lowering drugs for the treatment of T2DM in adult patients., Dapagliflozin 10 mg is recommended as a starting dose in adult patients with T2DM and in patients with severe hepatic impairment. In addition, dapagliflozin has protective renal and CV effects; and recently its use has been approved by the Drugs Controller General of India for patients with heart failure with reduced ejection fraction, and in CKD with or without T2DM.
This study compared the bioequivalence of a once-daily dose of two dapagliflozin 10 mg formulations, a test and reference product. This study found that 90% CI for AUCt and AUCinf were within the bioequivalence acceptable range of 80% to 125%. Moreover, the Cmax profile of dapagliflozin 10 mg was almost identical for test and reference products. The test product was well tolerated by all the volunteers under fasting conditions. All the adverse events were mild to moderate and did not cause study withdrawal.
In general, the values of dapagliflozin PK parameters obtained in this study were similar to the previously reported values after the administration of 10 mg dapagliflozin in healthy Caucasian volunteers under fasting conditions. A previous bioequivalence study of dapagliflozin 10 mg reported that Cmax, AUCt, and AUCinf of Cmax, AUCt, and AUCinf of 85.47 ng/mL, 495.13 hr*ng/mL, and 498.92 hr*ng/mL, respectively; as compared to reference 81.65 ng/mL, 480.92 hr*ng/mL, and 484.02 hr*ng/mL, respectively.
In the present study, Cmax was attained within 1 h after the administration of dapagliflozin under fasting state and t1/2 was 8.52 h. On the other hand, a study by Oroian et al. reported Cmax within 2 h and t1/2 of 14.04 h.
In this study, there were no reports of genital or urinary tract infection, possibly due to single-dose administration in both the study periods. Dapagliflozin is associated with a low risk of hypoglycemia and it reduces both weight and blood pressure. The importance of bioequivalence studies is increasing mainly because of the growing demand for generic products and their cumulative use. Generic medicines (test products) are way more economical than the branded formulations (reference product). Therefore, the use of the generic drug is suggested to reduce health-care expenditure while improving patient compliance. Previous studies have shown that the addition of dapagliflozin is cost-effective treatment and improves medication adherence in patients with or without diabetes., In 2020, dapagliflozin was available in India in the form of a generic drug and the resulting cost utility is benefiting many eligible patients. A cross-sectional questionnaire survey was conducted to report the cost-effectiveness of dapagliflozin in patients with T2DM and the complications arising as well. A total of 39% of the physicians opined that treatment discontinuation was observed in 20%−40% of patients due to high cost. A majority of patients reported that the low-cost dapagliflozin is affordable and can be used for the primary prevention of heart failure in patients with T2DM. Further, this study indicated that switching to low-cost dapagliflozin from other expensive SGLT2 inhibitors is a long-term cost-effective treatment for T2DM management. Generic dapagliflozin may provide similar benefits to that of innovator dapagliflozin, including metabolic benefits, cardioprotection, and nephroprotection. The use of the generic form of dapagliflozin will help in better management of T2DM in India, as per day cost and overall cost of treatment will be reduced. The clinical efficacy of generic dapagliflozin has been recently evaluated. Generic dapagliflozin showed similar efficacy outcomes, including levels of HbA1c (P = 0.95), FBS (P = 0.89), BMI (P = 0.38), serum creatine (P = 0.96), and the incidence of genital mycotic infections (6.8% versus 7.4%) and urinary tract infections (4.1% versus 3.9%) prior to shifting from an innovator brand. The majority of patients, irrespective of socioeconomic condition, geography may avail metabolic, cardiovascular, and renal benefits with affordable generic dapagliflozin.
The authors acknowledge the following limitation of this study. In this study, 10 mg of dapagliflozin tablet developed by MSN Laboratories Private Limited, India was evaluated; care must be taken when generalizing these results, as we do not comment on other generic brands of dapagliflozin.
| Conclusion|| |
The test product 10 mg dapagliflozin was bioequivalent with the reference product 10 mg Farxiga® (dapagliflozin) tablets in healthy adult patients under fasting conditions. The availability of low-cost dapagliflozin has the potential to improve clinical outcomes in millions of patients in India because of its renoprotective, cardioprotective, and glucose-lowering effect. This bioequivalence study will be an additional option for the democratization of diabetes care. Using bioequivalent preparations that are not only effective but economical as well will allow the benefits of SGLT2 inhibition to be shared with a much larger number of people with T2DM.
The medical writing support was provided by Ms. Snehal Khanolkar from Sqarona Medical Communications LLP (Mumbai), funded by USV Private Limited, Mumbai, India.
Financial support and sponsorship
The study was funded by MSN Laboratories, India.
Conflicts of interest
There are no conflicts of interest.
All the authors have contributed equally to the work and fulfill ICMJE authorship criteria. All the authors have reviewed the final draft and approved the same.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]