Author byline as per print journal: Chuei Wuei Leong¹, PhD; Elton Sagim¹, BBiomedSc; Kar Ming Yee¹, BPharm; Muhammad Shalhadi Saharuddin¹, BSc; Nik Mohd Zulhakimi Nik Abdullah¹, BSc; Noramirah Farhanah Saberi¹, BSc; Rajavikraman Boopathy¹, DipSc; Shahnun Ahmad¹, MBBS; Atiqah Amran¹, BSc; Raman Batheja², PhD; Rajan Sharma²>, MBBS; Kiran Kumar Vuppalavanchu², MPharm

Submitted: 15 September 2022; Revised: 7 November 2022; Accepted: 21 November 2022; Published online first: 5 December 2022

Introduction/Study Objectives

Diabetes mellitus is a multifactorial disease impacting different organ systems [1]. Until 2021, diabetes mellitus has affected 536.6 million people (10.5% of the world’s population between 20–79 years old). These numbers are expected to rise to 783.2 million people (12.1% of the world’s population), leading to severe health and economic burden [2]. Type 2 diabetes mellitus (T2DM) accounted for more than 95% of diabetes mellitus incidents [3]. T2DM is characterized by cells’ resistance to insulin resulting in elevated blood glucose levels [1] and is associated with high morbidity and mortality mainly due to its microvascular and macrovascular complications [4, 5]. T2DM requires effective glycaemic control generally achieved by lifestyle modifications and oral hypoglycaemic agents, which are considered to be the first line, especially when the β cells further deteriorate as the disease progresses with time [1].

Sitagliptin is a potent and selective dipeptidyl-peptidase (DPP-4) inhibitor, listed in 2017 among the top 20 drugs for T2DM treatment [6]. Like other DPP-4 inhibitors, sitagliptin deactivates the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide, which increases and extends the activity of incretin resulting in a glucose-dependent secretion of insulin and inhibition in glucagon [7]. Sitagliptin decreases not only the HbA1c but also the fasting and postprandial glucose [8]. Furthermore, it is safe to be used in combination with other oral hypoglycaemic agents with no additional risk of hypoglycaemia or weight gain [9].

Sitagliptin is absorbed rapidly with a median time to the maximum concentration (T_max) of 1–4 hours and an elimination half-life (T_1/2) of 8–14 hours [10, 11]. The area under the curve (AUC) of sitagliptin was found to increase in a dose-dependent manner in healthy volunteers [11], and its absolute bioavailability was 87% [12, 13]. The metabolism pathways of sitagliptin are mainly through oxidation in the liver via cytochrome P450 (CYP) 3A4 isoenzymes, with a secondary role from CYP2C8 [12]. Sitagliptin is excreted unchanged in urine (87%) and feces (13%) [12, 13]. Furthermore, it undergoes active tubular secretion in the kidney with a renal clearance recorded as 388 mL/min [11], which is why it can be foreseen that the pharmacokinetics of sitagliptin are largely affected by renal function [14]. On the other hand, in the presence of a creatinine clearance between 50 mL/min and 80 mL/min, classified as a mild renal impairment, no dose adjustment is needed because it was not found to have any clinically significant impact on sitagliptin pharmacokinetics [14].

Phase I clinical studies failed to demonstrate the pharmacokinetic interactions between sitagliptin and simvastatin, metformin, oral contraceptives, warfarin, glyburide, or rosiglitazone likely due to the sitagliptin’s lower affinity for CYP3A4, CYP2C8, and CYP2C9 [15–20]. Digoxin AUC_(0–24) was found to be increased by 11% and 18% with the administration of 100 mg and 200 mg sitagliptin, respectively [21]. However, it was not likely to be clinically significant [21]. The absence of interactions between 83 concurrently administered medications and sitagliptin was also demonstrated in a population pharmacokinetic model of phase I and phase IIb studies [22].

From a pharmaceutical perspective, the generic formulation can produce equally effective treatments potentially at lower cost, provided that it has identical active pharmaceutical ingredients and a comparable pharmacokinetic profile [23]. This study aimed to evaluate the bioequivalence in terms of exposure of a test formulation with a reference formulation each containing sitagliptin phosphate monohydrate equivalent to 100 mg sitagliptin. The study was conducted in fulfillment of the requirements by the regulatory authorities to market the test formulation.

Methods

Study design

A study design of an open-label, balanced, randomized, two-treatment, two-period, two-sequence crossover in healthy adult human volunteers was employed to evaluate the pharmacokinetic bioequivalence of a two formulation of sitagliptin 100 mg. The two periods were separated by a washout period of five days.

The study was conducted at VerGo Pharma Research Pvt Ltd (Division VerGo Clinicals), Goa, India, in accordance with the Declaration of Helsinki, the International Conference on Harmonization–Good Clinical Practice, and the ASEAN Guideline for the Conduct of Bioequivalence Studies. This study was approved by Aavishkar Ethics Committee (Research ID: 789-18) on 22 June 2020. The study was also registered in the Thai Clinical Trial Registry (TCTR20220621004) on 20 June 2022. Prior to their enrolment in the study, informed consents were obtained from the subjects.

Study population

Recruitment of volunteers was carried out based on the fulfillment of the inclusion criteria of: 1) healthy, assessed by the medical check-up (medical history, basic medical check-up, electrocardiogram (ECG), and laboratory findings (complete blood count, serological tests, biochemical tests, and urine analysis) performed prior to participation; 2) adults aged between 18 yrs and 55 yrs; 3) body mass index (BMI) of 18.5 kg/m² to 30 kg/m² with weight not less than 50 kg for males and 45 kg for females; 4) non-pregnant women; 5) non-smokers or smokers with less than ten cigarettes per day; 6) non-alcoholic individuals. Participants taking any prescription medications for the last 14 days or any over-the-counter medication for the last seven days before the initiation of the study; having any allergies or hypersensitivity to sitagliptin, those who consumed grapefruit juice in the 48 hours or caffeinated drinks 24 hours before the initiation of the study, and participants with drug abuse were excluded.

Based on the literature, the maximum intra-subject coefficient of variation (ISCV) in C_max was found to be 19% [24] and considering a power of at least 80% and a significance level of 5%, the sample size of 28 subjects was considered to be sufficient to establish pharmacokinetic bioequivalence between the formulations considering possible withdrawal and dropouts.

Study products and administration

In the present study, the pharmacokinetic bioequivalence of Fortesia^® tablets (containing 100 mg of sitagliptin) manufactured by Duopharma, Malaysia (test formulation) was compared with Januvia^® tablets (containing 100 mg of sitagliptin) manufactured by Merck Sharp & Dohme Ltd, England (reference formulation). After overnight fasting of at least 10 hours, volunteers were randomly allocated to take the test or reference products with 240 mL of water. Participants were instructed to remain seated for two hours after receiving the dose of the test or reference products. All participants received standard meals at a fixed schedule during the course of the study.

Sampling

A total of 20 blood samples (4 mL each) were collected from each volunteer at pre-dose and 0.5, 1, 1.3, 1.7, 2, 2.3, 2.7, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 16, 24, 34, and 48 hours post-dose into K₂-ethylenediaminetetraacetic acid vacutainers. Centrifugation was then performed at 4,000 revolutions per minute (RPM) for 10 minutes at 10°C. After its separation, plasma was stored in the freezer (-30°C ± 10°C), then transferred to the bioanalytical department of VerGo clinicals, where it was stored in a freezer (-70°C ± 15°C) until the analytical analysis was carried out.

Subject monitoring

Clinical and laboratory investigations were carried out to assess the safety and report any adverse events observed during the study. Vital were monitored at time of check in, before drug administration and at 2 hours, 6 hours, and 11 hours before check out and before each ambulatory sample collection in each period. In each period subject’s blood glucose monitoring was performed before dosing and at 1 hours, 3 hours, and 7 hours (± 30 minutes) after dosing.

Determination of sitagliptin plasma concentrations

Analytical method for estimation of sitagliptin in human plasma was developed and validated using liquid chromatography and tandem mass spectrometry (LC-MS/MS) with positive ion electrospray ionization using selected reactions monitoring (SRM) mode (Shimadzu, Japan). Plasma extraction was performed through the solid-phase extraction method using Strata™-X 33µm polymeric sorbent cartridges. 10 µL of the sample was injected via the autosampler, and separation was done using a HyPURITY C8 column (100 mm × 4.6 mm, i.d.: 5µm) at a temperature of 40°C and a 0.8 mL/min flow rate of the mobile phase consisting of acetonitrile and 0.1% formic acid (70:30, v/v). Sitagliptin and internal standard were monitored at the molecular ion 408.2–412.2 m/z and MS/MS (daughter) 235.1–239.1 m/z. Sitagliptin D4 was used as an internal standard. Analyte quantitation was performed on a triple quadrupole mass spectrometer using atmospheric pressure ionization (API), operated in multiple reaction monitoring (MRM) and positive ion mode. The method was validated in the concentration range of 2.024–800.714 ng/mL with good linearity of r² equals 0.999. The method achieved a within- and between-day CV% of less than 5.3% and 4.3%, respectively, and an accuracy of 93%–110%. Recovery was 78.2%–83.1% for both the internal standard and the analyte. The lower and upper limits of quantification (LLOQ and ULOQ) were found to be 2.0 ng/mL, and 800.7 ng/mL, respectively.

Pharmacokinetic and statistical analysis

Treatments were allocated to subjects by carrying out randomization using SAS software. To eliminate any bias resulting from the open-label study design, the bioanalytical department performing the bio-analysis was blinded for the identity of reference and test, and the sample analysts were blinded for the randomization schedule. Non-compartmental pharmacokinetic analysis was performed through the Phoenix WinNonlin version 6.3 (Pharsight Corporation, USA) to estimate pharmacokinetic parameters such as the AUC, 0 to infinity (AUC_0-inf), AUC, 0 hours to 48 hours (AUC_0-48), maximum concentration (C_max), elimination constant (K_e), T_max, and T_1/2 of the drug. Statistical analysis was performed via SAS software version 9.4 (SAS^® Institute Inc., USA, Version 9.4), where multivariate analysis of variance (ANOVA) was carried out on the Ln-transformed pharmacokinetic parameters C_max, AUC_0-48, and AUC_0-inf with treatment, period, sequence and subjects nested within the sequence as a fixed effect. The BE of the test formulation with the reference product was assessed based on an alpha value of 0.05, i.e. within a 90% confidence interval (CI).

Results and discussion

The present work investigated the pharmacokinetic bioequivalence of a test product formulation with a reference formulation both containing 100 mg of sitagliptin in 28 healthy volunteers under fasting conditions. One volunteer withdrew before receiving the dose in the first period due to a medical event (nausea followed by one episode of vomiting). Twenty-seven volunteers had completed the study, and their data were included in the analysis. Table 1 summarizes the demographic characteristics of the healthy volunteers with a mean ± standard deviation age of 27.0 ± 5.9 years and BMI of 23.1 ± 2.8 kg/m². Regarding safety, no serious adverse events were reported during the study. Two volunteers had red blood cells count below the normal range, one of them had elevated aspartate transaminase levels (AST), and another volunteer had increased eosinophils count. The reported adverse events were mild, and they resolved without any sequelae. The adverse events were unlikely due to the investigational product. The elevated AST was rarely reported with sitagliptin use only in a single case in the literature provoked by a possible interaction with the hepatitis B virus [25]. However, multiple reports of the increased eosinophils count were available and were possibly related to the sitagliptin pharmacological effect of DPP-4 inhibition [26, 27].

The crossover study design involved five days washout step between the two periods adequate to account for at least 10 half-lives of sitagliptin to avoid the carryover phenomenon. The pharmacokinetic parameters of the test and reference formulations, i.e. AUC_0-48, AUC_0-inf, T_max, C_max, and T_1/2, are summarized in Table 2. C_max, AUC_0-inf, and AUC_0-48 values were comparable between the test and reference formulation. Additionally, intrasubject variabilities in AUC_0-48 were found to be 16.5% and 19.1%, and AUC_0-inf, 16.7% and 19.2%, and C_max, 24.1% and 27.6%, for the test and reference formulation, respectively. The pharmacokinetic profile found in other pharmacokinetic bioequivalence studies of a single dose of sitagliptin 100 mg or 500 mg tablets alone or in combination with metformin performed in the Asian population in terms of AUC_0-inf [28, 29], T_1/2 [29-31], and T_max [32] was comparable with the present results. Similar results in terms of T_max [33] and C_max [22] have also been reported in previous pharmacokinetic bioequivalence studies of a single dose of sitagliptin 50 mg [33] and 100 mg [22] tablet in American Hispanic/Latino and non-Hispanic/Latino volunteers. The current results were also in line with ones reported in European volunteers in the original study investigating the pharmacokinetics, pharmacodynamics, safety, and tolerability of single doses of sitagliptin ranging between 1.5 mg and 600 mg [11]].

Figure 1 represents the mean plasma concentration of sitagliptin in the plasma for the test and reference formulations versus the time profiles in 27 healthy volunteers (all below the limit of quantification data points were inserted as zero and were involved in the calculation of means). The median T_max was comparable between the two formulations based on the current results. The elimination of sitagliptin occurred gradually during the sampling interval of 48-hour. The differences in C_max, AUC_0-inf, or AUC_0-48 between the reference and test formulation were found to be not significant based on the multivariate ANOVA statistical analysis. The 90% CIs of the Ln-transformed AUC_0-48, AUC_0-inf, and Cmax, were 99.2%–103.3%, 99.2%–103.2%, and 95.6%–108.7%, respectively. The two-sided 90% CIs of Ln-transformed AUC_0-48, AUC_0-inf, and Cmax of sitagliptin were within the pharmacokinetic bioequivalence acceptance range of 80%–125%, according to the ASEAN Guideline for the Conduct of Bioequivalence Studies [34].

The pharmacokinetic profile of sitagliptin found in the current study may represent the Asian population as only Asian participants were included affecting the generalizability of the results in different populations. However, the inter-individual variability was addressed in the randomized crossover study design eliminating its effect on the pharmacokinetic bioequivalence of the study products, i.e. it can be concluded that the pharmacokinetic profiles of test and reference products were similar in terms of absorption, distribution, metabolism, and elimination. The pharmacodynamic bioequivalence was not investigated in the current study and could be a potential topic for future studies in patients as complementary to the exposure term.

Conclusion

The pharmacokinetic bioequivalence of a single dose test product with a reference product, each containing 100 mg sitagliptin under fasting conditions, was confirmed in the present study in terms of AUC_0-inf, AUC_0-48, and C_max. The 90% confidence intervals of sitagliptin Ln-transformed AUC_0-inf, AUC_0-48, and C_max, were within the pharmacokinetic bioequivalence acceptance range of 80%–125%. The study was in fulfillment of the requirements by the regulatory authorities to market the test formulation.

Funding sources

This work was financially supported by Duopharma Biotech Berhad.

Competing interests: CWL, ES, KMY, MSS, NMZNA, NFS, RB, SA, and AA are employees of Duopharma. RB, RS, and KKV are employees of VerGo Pharma Research.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Chuei Wuei Leong¹, PhD
Elton Sagim¹, BBiomedSc
Kar Ming Yee¹, BPharm
Muhammad Shalhadi Saharuddin¹, BSc
Nik Mohd Zulhakimi Nik Abdullah¹, BSc
Noramirah Farhanah Saberi¹, BSc
Rajavikraman Boopathy¹, DipSc
Shahnun Ahmad¹, MBBS
Atiqah Amran¹, BSc
Raman Batheja², PhD
Rajan Sharma², MBBS
Kiran Kumar Vuppalavanchu², MPharm

¹Duopharma Innovation Sdn Bhd, No. 2, Jalan Saudagar U1/16, Zon Perindustrian Hicom Glenmarie, Seksyen U1, Shah Alam, 40150, Selangor, Darul Ehsan, Malaysia
²VerGo Pharma Research Pvt Ltd (Division VerGo Clinicals), Goa 403110, India

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