Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Relative to Originator

A Bioequivalence Study of Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Relative to Originator in Healthy Thai Volunteers Under Fed Condition.

The study is to compare the rate and extent of absorption of a generic formulation with that of a reference for mulation when given as equal labeled dose. The study will be randomized, open-label, single dose, two way crossover design with two-period, two-treatment and two-sequence under fed condition and at least 7 days washout period between the doses.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Test product; Drug: Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Reference product

Detailed Description

Title A Bioequivalence study of a randomized, open-label, single dose, two-way crossover design with two-period, two-treatment and two-sequence of Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg relative to Originator Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg in healthy Thai volunteers under fed condition.

Objectives The primary objective is to compare the rate and extent of absorption of a generic formulation with that of a reference formulation when given as equal labeled dose. The secondary objective is to evaluate the safety after oral administration of both test and reference formulation in healthy Thai volunteers.

Study Design Randomized, open-label, single dose, two-way crossover design with two-period, two-treatment and two-sequence under fed condition and at least 7 days washout period between the doses.

Sample Size 34 Healthy Human Thai subjects. Two extra subjects if available, may be checked-in on the day of check in of period-I to compensate for any dropout prior to dosing of period-I. These subjects will be dosed if there are dropouts prior to dosing in period-I. If there are no dropouts, these subjects will be checked-out without being dosed after completion of dosing in period-I.

Drug-Product Test-Product: Sitagliptin and Metformin tablets 50 mg/500 mg Reference-product: Sitagliptin and Metformin tablets 50 mg/500 mg Manufactured by: Patheon Puerto Rico, Puerto Rico 00674

Administration After an overnight fasting at clinical facility of at least 10 hours, each volunteer will receive high fat high calories breakfast which they are required to consume within 30 minutes and then a single dose of Sitagliptin and Metformin tablets 50 mg/500 mg of either test or reference with 250 mL of 20% glucose solution in water within 30 mins after starting the high fat high calories breakfast. Each volunteer will be allowed to drink water as desired except 1 hour before and after drug administration. The formulation is given in a crossover fashion as per the randomization schedule. After the administration, the subject's oral cavity will be checked by using flashlight to confirm complete medication and fluid consumption by pharmacist.

Blood Schedule In each period, a total of 23 blood samples (approximately 5 mL each) will be collected pre-dose (0.00 hour) and at 0.333, 0.667, 1.000, 1.500, 2.000, 2.500, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.000, 5.500, 6.000, 7.000, 8.000, 10.000, 12.000, 24.000, 36.000 and 48.0000hours after study drug administration, respectively. The sample collection at 24.00, 36.00 and 48.00 hours after dosing will be on ambulatory basis (i.e. on separate visit.).

Sample Collection Blood samples will be collected through an indwelling catheter placed in a vein using disposable syringe or through fresh venipuncture with disposable syringes and needles. Approximately 5mL blood sample will be withdrawn and transferred to sample collection pre-labeled tubes containing K3EDTA as anticoagulant at each sampling time point. After collection of blood samples from each subject at each time point, samples will be centrifuged at 4000 rpm for 5 minutes at 4±2°C. After centrifugation, the plasma samples will be aliquoted into two pre-labeled cryovials for approximately 1 mL in original cryovial and leaving the remaining volume for the duplicate cryovial. Cryovials containing plasma sample will be stored at -70±10 °C.

Analytical Method Sitagliptin and Metformin plasma concentration will be assayed as per international Guidelines/In-house SOP by using a validated LC-MS/MS method.

Pharmacokinetic Parameters Primary pharmacokinetic parameter: Cmax, AUC0→t and AUC0→∞ Secondary pharmacokinetic parameter: Tmax, T1/2, Kel, AUC0→t/AUC0→∞ will be determined from the plasma concentration data of analytes.

Statistical Analysis ANOVA, two one-sided tests for bioequivalence, for log-transformed pharmacokinetic parameters Cmax, AUC0→t and AUC0→∞ will be performed.

Acceptance Criteria for Bioequivalence To be considered as bioequivalent, the 90% Confidence Interval of the geometric means ratio of Cmax, AUC0→t and AUC0→∞ of Sitagliptin and Metformin of test and reference products should be in the interval of 80.00-125.00% for the log-transformed data.

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sasitorn Kittivoravitkul, Ph.D.; Phone Number: 022549008; Email: sasitorn_k@bio-innova.com
• Study Contact Backup: Name: Somkiat Tatritorn, M.D.; Phone Number: 022549008; Email: somkiat_t@bio-innova.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Willingness to provide written informed consent prior to participate in the study.
2. Healthy Thai subjects are between 18 to 55 years of age.
3. The Body Mass Index (BMI) ranges from 18.5 to 30 kg/m2.
4. Comprehensive of the nature and purpose of the study and compliance with the requirement of the entire protocol and allow investigators to draw 7 mL of blood for monitoring subjects' safety after the completion of the study.
5. Negative urine pregnancy test for women and no breast-feeding.
6. Absence of significant diseases or clinically significant abnormal laboratory values on the laboratory evaluations, medical history or surgery during the screening. Some of the laboratory values e.g. Complete blood count etc. that out of the normal range will be carefully considered by physician.

Exclusion Criteria:

1. History or evidence of allergy or hypersensitivity to Sitagliptin, Metformin or any related drugs or any of the excipients of this product.
2. Subject with B.P. is Systolic B.P < 90, ≥140 mm/Hg, Diastolic B.P < 60, ≥90 mm/Hg, pulse rate > 100 beats per minute.
3. Serum bilirubin greater than 1.5 times the upper limit of reference range (ULRR).*
4. Serum creatinine greater than 1.5 times the upper limit of reference range (ULRR).*
5. Alanine amino transferase (ALT) or aspartate amino transferase (AST) greater than 2 times the upper limit of reference range (ULRR).*
6. Positive of hepatitis B or C virus.
7. Have more than one abnormal EKG, which is considered as clinically significant. *
8. History or evidence of heart, renal, hepatic disease, pulmonary obstructive disease, bronchial asthma, hypertension or glaucoma
9. History or evidence of gastrointestinal disorder likely to influence drug absorption or previous GI surgery other than appendectomy.
10. History or evidence of hypoglycemia before drug administration of each period.*
11. Any major illness in the past 3 months or any significant ongoing chronic medical illness.
12. History of psychiatric disorder.
13. History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) and cannot stop at least 2 days before the study drug administration and until the completion of each period of the study.
14. History of usually smoking (more than 10 cigarettes per day within past 1 year), if moderate smokers (less than 10 cigarettes per day) cannot stop at least 7 days before the study drug administration and until the completion of the study.
15. High caffeine consumption (more than 5 cups of coffee or tea per day) and cannot stop at least 2 days before the study drug administration and until the completion of each period of the study.
16. History of grapefruit, pomelo or grapefruit products consumption and cannot stop at least 7 days before the study drug administration and until the completion of the study.
17. Positive drug abused test in urine (Benzodiazepines, Marijuana (THC), Methamphetamine, Cocaine and Opioids).
18. Receipt of any prescription drug therapy within 14 days or 5 half-lives (whichever longer) preceding the first dose of study medication or over-the-counter (OTC) drugs or herbal medicines/food supplement within 7 days or hormonal methods of contraception within 28 days (Depo-Provera must be discontinued at least 6 months) prior to the study drug administration and until the completion of each period of the study.
19. History of difficulty in accessibility of veins in left and right arm.
20. Blood donation (one unit or 450 mL) within the past 3 months before the study.
21. Participation in any clinical study within the past 3 months before the study.
22. Subjects who are unwilling or unable to comply with the lifestyle guidelines described in this protocol.

(* Depend on decision of principal investigator and/or clinical investigator)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1-Sitagliptin and Metformin Hydrochloride Tablets test product; Participants will receive treatment 1 in period 1 and treatment 2 in period 2. Where treatment 1= Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg test product, treatment 2= Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg reference product.	Drug: Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Test product; Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Manufactured by: Mankind Pharma Limited, India
Experimental: Sequence 2-Sitagliptin and Metformin Hydrochloride Tablets reference product; Participants will receive treatment 2 in period 1 and treatment 1 in period 2. Where treatment 1= Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg test product, treatment 2= Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg reference product.	Drug: Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Reference product; Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Manufactured by: Patheon Puerto Rico, Puerto Rico 00674

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC 0-t)	pre-dose (0.00 hour) and at 0.333, 0.667, 1.000, 1.500, 2.000, 2.500, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours post-dose	Blood samples will be collected for PK analyses in pre-dose and at 0.333, 0.667, 1.000, 1.500, 2.000, 2.500, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours post-dose
Maximal measured plasma concentration (Cmax)	pre-dose (0.00 hour) and at 0.333, 0.667, 1.000, 1.500, 2.000, 2.500, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours post-dose	Blood samples will be collected for PK analyses pre-dose (0.00 hour) and at 0.333, 0.667, 1.000, 1.500, 2.000, 2.500, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with adverse events	An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	Approximately the day 14 after the last visit

Collaborators and Investigators

• Sponsor: Bio-innova Co., Ltd

Study record dates

Study Major Dates

• Study Start (Estimated): June 4, 2024
• Primary Completion (Estimated): July 14, 2024
• Study Completion (Estimated): July 28, 2024

Study Registration Dates

• First Submitted: December 15, 2023
• First Submitted That Met QC Criteria: January 22, 2024
• First Posted (Actual): January 31, 2024

Study Record Updates

• Last Update Posted (Actual): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Sitagliptin Phosphate
• Other Study ID Numbers: SME-033-23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Company Policy

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No