Abstract
OBJECTIVE:
The purpose of this study was to compare the Pharmacokinetics of Sitagliptin 100 mg tablets in healthy Asian Indian and Thai Volunteers.
MATERIALS AND METHODS:
Two independent crossover evaluations were conducted in healthy adults of Indian (Study 1) and Thai (Study 2) origin. Participants received a single 100 mg dose of either test or reference sitagliptin tablet under fasting conditions, followed by the alternate product after a washout. Plasma sitagliptin was quantified by validated LC-MS/MS, and non-compartmental analysis yielded Cmax, AUC0–t, AUC0–∞, and Tmax. Bioequivalence was concluded when 90% confidence intervals (CIs) for geometric mean ratios fell within 80%–125%.
RESULTS:
For both Indian and Thai cohorts, point estimates and 90% CIs for Cmax, AUC0–t and AUC0–∞ were contained in predefined 80%–125% interval, and no clinically meaningful differences between formulations were detected. Exposure metrics were comparable across the two ethnic groups.
CONCLUSIONS:
In the two studies conducted in healthy Asian Indian and Thai volunteers, the test and reference formulation of sitagliptin 100 mg exhibited comparable pharmacokinetics profiles and were bioequivalent according to the regulatory definition based on rate and extent of absorption. Both formulations were well tolerated by all volunteers. Similar Cmax and AUC values were observed across both populations, indicating that ethnicity has no significant effect on the pharmacokinetics of sitagliptin. Therefore, bioequivalence results obtained in one population can be extrapolated to others.
Keywords: Bioequivalence, healthy volunteers, pharmacokinetic, sitagliptin
Introduction
Sitagliptin (MK-0431 [(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro [1,2,4] triazolo[4,3-a]-pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl) butan-2-amine]) is an orally active, potent and selective inhibitor of DPP-IV.[1] It is available in more than 130 countries worldwide under various brands of Sitagliptin, such as Januvia, Xelevia, Glactiv, Tesavel. Sitagliptin is used as monotherapy or in combination with other antidiabetic drugs for the treatment of type 2 diabetes.[2] By preventing DPP4 from deactivating the endogenous incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, sitagliptin enhances glycemic control. Both hormones improve the insulin response in a glucose-dependent manner and suppress the postprandial glucagon response following food intake.[3,4,5]
It is available as round, film-coated tablets containing sitagliptin phosphate monohydrate, corresponding to 25, 50 and 100 mg of sitagliptin.[6] Sitagliptin, when given orally, is rapidly absorbed after a single 100 mg dose in healthy adult volunteers, with peak plasma concentrations attained 1–4 h post dose. With single doses of sitagliptin (25–400 mg) in healthy volunteers, AUC0–∞ increased in a dose-proportional manner.[7,8,9] The absolute bioavailability of sitagliptin is 87%, and its oral absorption is not affected by food; hence, the drug may be taken without regard to meals.[7,8,10]
[14C]-sitagliptin was shown to be eliminated by biliary and/or renal excretion of the parent drug in the preclinical studies.[11] It mainly involved N-sulfation (M1), N-carbamoyl glucuronidation (M4), hydroxylation (M6), followed by ether glucuronidation (M3), and oxidative desaturation followed by cyclization (M2 and M5), whereas the metabolism was minimal.[12] In humans, metabolism of sitagliptin is mainly by the CYP3A4, which is the primary enzyme, and CYP2C8 also contribute in the metabolism. In normal renal function patients, metabolism plays only a minor role in the overall clearance of sitagliptin.[8]
Although a study on bioequivalence of sitagliptin in healthy Thai volunteers has been published previously, but not available in the public domain.[13]
For the first time, the pharmacokinetic results of sitagliptin in Thai and Asian Indian volunteers are compared in this paper. The objective of this study was to demonstrate the bioequivalence between the test formulation (Sitagliptin of Sun Pharmaceutical Industries, India) and the reference formulation of sitagliptin (JANUVIA of Merck Sharp and Dohme Ltd., United Kingdom) 100 mg tablet and also to evaluate the effect of ethnicity on the pharmacokinetics of sitagliptin in healthy human volunteers. Two separate randomized, two-way, crossover, bioequivalence studies were conducted in healthy Thai and Asian Indian volunteers to compare the bioavailability of sitagliptin 100 mg tablets of a test and a reference product.
Materials and Methods
Study design and participants
Two stand-alone, randomized, two-period, two-sequence crossover studies were undertaken: Study 1 in healthy Asian Indian adults and Study 2 in healthy Thai adults. Eligibility criteria included age 18–55 years and BMW 18.50–30.00 kg/m2, with normal findings on medical history, examination, electrocardiogram and clinical laboratory tests. All participants provided written informed consent, and protocols complied with the Declaration of Helsinki and Good Clinical Practice.
Treatments and study conduct
Within each study, participants received a single oral dose of sitagliptin 100 mg as either the test or reference product in Period 1 and the alternate product in Period 2, separated by a washout (5 days in Study 1; 7 days in Study 2). Dosing occurred after an overnight fast with 240 mL of water; standardized meals were provided post-dose, and xanthine-containing beverages were avoided during confinement.
Blood sampling
Venous blood was collected through an indwelling catheter or venipuncture at predefined times:
Study 1 (Indian cohort): 0.000, 0.333, 0.667, 1.000, 1.333, 1.667, 2.000, 2.333, 2.667, 3.000, 3.333, 3.667, 4.000, 4.500, 5.000, 5.500, 6.000, 7.000, 8.000, 10.000, 12.000, 16.000, 24.000, 36.000, 48.000, and 72.000 h
Study 2 (Thai cohort): 0.000, 0.333, 0.667, 1.000, 1.333, 1.667, 2.000, 2.333, 2.667, 3.000, 3.333, 3.667, 4.000, 4.500, 5.000, 5.500, 6.000, 8.000, 10.000, 12.000, 16.000, 24.000, 36.000, and 48.000 h, respectively.
Bioanalysis
Plasma sitagliptin concentrations were determined using a validated LC-MS/MS method. Assay met acceptance criteria for calibration range, accuracy, and precision according to bioanalytical standards.
Pharmacokinetic and statistical analysis
Noncompartmental analysis was performed (WinNonlin) to obtain Cmax, AUC0–t, AUC0–∞, and Tmax. Bioequivalence between test and reference was assessed separately within each study using ANOVA on log-transformed Cmax, AUC0–t and AUC0–∞ to estimate geometric mean ratios and 90% CIs, with the conventional 80%–125% criterion defining equivalence. Exploratory comparisons of exposure between Indian and Thai cohorts (including subgroup analysis) were conducted.
Ethical approval
The study protocol was approved.
Results
Demographic data
42 Asian Indian population enrolled in Study 1, and 40 Thai volunteers enrolled in Study 2. The age criteria and body mass index for both studies are summarized in Table 1.
Table 1.
Demographic characteristics of enrolled subjects
| Characteristics | Study 1 (Asian Indian volunteers) | Study 2 (Thai volunteers) |
|---|---|---|
| Age (years) | 18–45 years | 18–55 years |
| Weight/BMI | 18.50–30.00 kg/m2 | 18.50–30.00 kg/m2 |
| Number of healthy subjects | 42 (41 completed) | 40 (39 completed) |
| Gender | 42 males | 18 female and 21 male |
BMI=Body mass index
Pharmacokinetic and statistical analysis and ethnicity/race by formulation effect
Based on data from both studies, sitagliptin achieved a mean Cmax of approximately 491 ng/ml in Study 1 and 448 ng/ml in Study 2. The mean plasma concentration profile and pharmacokinetic parameters for both studies are summarized in the figures and tables.
Discussion
The objective of this article is to demonstrate the bioequivalence between the test and reference formulations of the sitagliptin 100 mg tablet and to evaluate the effect of ethnicity on the pharmacokinetics of sitagliptin in healthy human volunteers. Two formulations of the same drug are considered to be bioequivalent and therapeutically equivalent if they exhibit a comparable extent and rate of absorption when administered at the same molar dose under similar experimental conditions.
Both Studies 1 and 2 were conducted on healthy volunteers in accordance with the study protocol. Both sitagliptin formulations (test and reference) were well tolerated by all subjects in both studies. The mean plasma concentrations-time profiles for the two formulations over the 72-h sampling period in Study 1 and the 48-h sampling period in studies 2 are presented in Figures 1 and 2, respectively.
Figure 1.
Mean plasma concentration-time profile following administration of both sitagliptin formulations in Asian Indian volunteers (study 1)
Figure 2.
Mean plasma concentration-time profile following administration of both sitagliptin formulations in Thai volunteers (study 2)
Descriptive statistics of the pharmacokinetic parameters (AUC0–t, AUC0–∞, Cmax, and Tmax) for the test and reference formulations of Studies 1 and 2 are summarized in Tables 2 and 3.
Table 2.
Mean pharmacokinetic parameters (±standard deviation) following administration of two sitagliptin formulations in Asian Indian volunteers (study 1)
| Pharmacokinetic parameter | Reference formulation (A) | Test formulation (B) | n |
|---|---|---|---|
| Cmax (ng/mL) | 491.14±130.81 | 511.96±113.13 | 41 |
| AUC0-t (ng × h/mL) | 4447.79±829.80 | 4467.53±841.00 | |
| AUC0-∞ (ng × h/mL) | 4505.71±873.90 | 4522.53±848.95 | |
| Tmax (h) | 3.02±1.57 | 2.52±1.28 | |
| t1/2 (h) | 9.69±3.02 | 9.88±2.93 |
Table 3.
Mean pharmacokinetic parameters (±standard deviation) following administration of the two sitagliptin formulations in Thai volunteers (study 2)
| Pharmacokinetic parameter | Reference formulation (A) | Test formulation (B) | n |
|---|---|---|---|
| Cmax (ng/mL) | 448.33±131.30 | 459.29±143.27 | 39 |
| AUC0-t (ng × h/mL) | 3464.03±533.18 | 3518.95±566.03 | |
| AUC0-∞ (ng × h/mL) | 3559.35±538.69 | 3605.95±565.12 | |
| Tmax (h) | 2.48±1.30 | 2.69±1.24 | |
| t1/2 (h) | 8.08±1.70 | 7.71±1.77 |
In Study 1 (Asian Indian volunteers), the geometric mean ratio and 90% confidence interval (CI) for the Cmax were 105.29 (99.21–111.75), for AUC0-t were 100.43 (98.47–102.43) and for AUC0-∞ were 100.35 (98.41–102.33). In Study 2 (Thai volunteers), the corresponding geometric mean ratio and 90% CI were 101.86 (96.66–107.33) for Cmax, 101.47 (99.64–103.33) for AUC0-t and 101.21 (99.46–102.99) for AUC0-∞.
In Study 1, the maximum observed intra-subject coefficient of variation (ISCV) was 16.09% for the Cmax, and for the AUC0-t and AUC0-∞ the observed ISCV was around 5% in both studies.
We evaluated the effect of ethnicity/race by formulation on the study population as follows
Male Thai volunteers versus male Indian volunteers: For Cmax, AUC0-t and half-life (HL_Lambda_z), the observed P values were 0.1764 for Cmax, 0.6461 for AUC0-t and 0.4271 for half-life (HL_Lambda_z), all >0.05, indicating no statistically significant difference
Female Thai volunteers versus male Indian volunteers: For the Cmax, AUC0-t and half-life (HL_Lambda_z), the observed values were 0.6773 for Cmax, 0.1000 for AUC0-t and 0.2046 for the half-life (HL_Lambda_z), all >0.05, indicating no statistically significant difference
Total Thai volunteers versus total Indian volunteers: For the Cmax, AUC0-t and half-life (HL_Lambda_z), the observed values were 0.3679 for the Cmax, 0.0513 for AUC0-t and 0.2604 for half-life (HL_Lambda_z) again >0.05, suggesting no significant difference.
The results of the inferential statistical analysis for Studies 1 and 2 are summarized in Tables 4 and 5. Statistical comparison of the primary pharmacokinetic parameters (AUC0–t, AUC0–∞, and Cmax) indicate no significant differences between the test and reference formulations in either study, confirming bioequivalence.
Table 4.
Summary of statistical parameters following administration of two sitagliptin formulations in Asian Indian volunteers (study 1)
| Parameters | Ln (Cmax) (ng/mL) | Ln (AUC0-t) (ng × h/mL) | Ln (AUC0-∞) (ng × h/mL) |
|---|---|---|---|
| Ratio (%) | 105.29 | 100.43 | 100.35 |
| 90% CI’s | 99.21–111.75 | 98.47–102.43 | 98.41–102.33 |
| ISCV | 16.09 | 5.3 | 5.26 |
ISCV=Intra-subject coefficient of variation, CIs=Confidence intervals, AUC=Area under the curve
Table 5.
Summary of statistical parameters following administration of two sitagliptin formulations in Thai volunteers (study 2)
| Parameters | Ln (Cmax) (ng/mL) | Ln (AUC0-t) (ng × h/mL) | Ln (AUC0-∞) (ng × h/mL) |
|---|---|---|---|
| Ratio (%) | 101.86 | 101.47 | 101.21 |
| 90% CI’s | 96.66–107.33 | 99.64–103.33 | 99.46–102.99 |
| ISCV | 13.75 | 4.76 | 4.57 |
ISCV=Intra-subject coefficient of variation, CIs=Confidence intervals, AUC=Area under the curve
The parametric 90% CIs for these pharmacokinetic parameters were entirely within the bioequivalence acceptance range of 80%–125%.
When comparing the results of both studies, similar values for Cmax and AUC were observed in Asian volunteers and Thai volunteers [Tables 2 and 3]. Furthermore, no significant ethnicity/race by formulation effect was observed in the study population [Table 6].
Table 6.
Effect of ethnicity/race by formulation on the respective study population, as summarized in table below
| Thai volunteers | Indian volunteers | P value for Cmax | P value for AUC0-t | P value for half life |
|---|---|---|---|---|
| Male Thai volunteers | Male Indian volunteers | 0.1764 | 0.6461 | 0.4271 |
| Female Thai volunteers | Male Indian volunteers | 0.6773 | 0.1000 | 0.2046 |
| Total Thai volunteers | Total Indian volunteers | 0.3679 | 0.0513 | 0.2604 |
AUC=Area under the curve
The same formulation was tested in Asian Indian and Thai volunteers; in both studies, similar relative bioavailability was observed for Cmax and AUC when compared with the reference product. These findings indicate that ethnicity has no impact on bioavailability and bioequivalence results observed in one population can be extrapolated to another. This assumption is further supported by the observation of similar pharmacokinetic profiles in Asian Indian and Thai subjects, confirming that ethnicity does not influence the pharmacokinetics of sitagliptin.
Conclusions
In the two studies conducted in healthy Asian Indian and Thai volunteers, the test and reference formulation of sitagliptin 100 mg exhibited comparable pharmacokinetics profiles and were bioequivalent according to the regulatory definition based on rate and extent of absorption. Both formulations were well tolerated by all volunteers. Similar Cmax and AUC values were observed across both populations, indicating that ethnicity has no significant effect on the pharmacokinetics of sitagliptin. Therefore, bioequivalence results obtained in one population can be extrapolated to others.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
The studies were fully supported by Sun Pharmaceutical Industries Ltd.
Funding Statement
Nil.
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