Bioequivalence Assessment Between Two Imeglimin Hydrochloride Film Coated Tablet Formulations

Open Label, Randomized, Single-dose, Two-sequence, Two-period, Crossover Study to Assess the Bioequivalence of Imeglimin HCl in Glimcoza 500 mg Film Coated Tablet (Test Product) in Comparison With Twymeeg® 500 mg Tablet (Reference Product) in Healthy Subjects Under Fasting Condition

An open label, randomized, single-dose, two-sequence, two-period, crossover study to assess the bioequivalence of Imeglimin HCl in Glimcoza 500 mg film coated tablet (Test product) in comparison with Twymeeg® 500 mg tablet (Reference product) in healthy 31 subjects under fasting condition.

This was a single-dose, open-label, randomized, two-sequence, two-period crossover bioequivalence study conducted under fasting conditions at Advanced Research Center (ARC), Cairo, Egypt in 2025. The study compared the bioequivalence of Imeglimin HCl in Glimcoza 500 mg film coated tablet (Test product) in comparison with Twymeeg® 500 mg tablet (Reference product), both formulations containing Imeglimin HCl. Study Design Participants were randomized in a 1:1 ratio to receive the test or reference product across two study periods, separated by a one-week washout. Each subject received a single oral dose (equivalent to 500 mg Imeglimin HCl) under fasting conditions. A standardized diet was provided during each period, and fluid intake was controlled pre- and post-dosing to maintain consistency. Blood Sampling Details In each period, 22 blood samples (5 mL each) were collected to characterize the plasma concentration-time profile. A forearm vein cannula was used for samples up to 24 hours; later samples were collected via venipuncture. Samples were centrifuged at 3500 rpm for 5 minutes at 4°C. Plasma was separated and stored at -80°C pending analysis. Pharmacokinetic and Bioanalytical Methods Plasma Imeglimin HCl concentrations were quantified using a validated LC-MS/MS method. The primary PK parameters included Cmax AUC(0-inf), and AUC(0-72), while secondary parameters were Tmax, t½, and kel. PK analysis was conducted using Phoenix WinNonlin (v8.3.4), with calculations based on actual sampling times. Bioequivalence Evaluation Bioequivalence was determined if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax AUC(0-inf), and AUC(0-72) fell within the 80-125% range. ANOVA was applied to log-transformed data for Cmax and AUC, and Wilcoxon signed-rank test was used for Tmax comparisons. Safety Evaluation Subjects were monitored for adverse events throughout the study. Vital signs were assessed at multiple time points (pre-dose, and 2, 4, 6, 12, and 72 hours post-dose). Complete blood counts were performed at the study's end. Statistical Analysis was performed using R (v4.2.1). The Two One-Sided Tests (TOST) procedure was applied to log-transformed PK parameters to assess bioequivalence.

Inclusion Criteria:

1. Healthy male and female subjects aged between 18 and 55 years.
2. Non-smokers or mild smokers with a maximum limit of 5 cigarettes/day.
3. Normal physical examinations at screening visit.
4. Having BMI ranged between 18.5-30 kg/m2.
5. Ability to communicate adequately with the clinical staff.
6. Ability and agreement to comply with the study requirements.
7. Normal BP and HR measured under stabilized conditions. • The Blood pressure is considered normal if the SBP falls within 100 to 140 mmHg, and the DBP within 60 to 90 mmHg. • The heart rate normal range is from 60 to 100 bpm. • Respiratory rate normal range is from 12 to 16 breaths per minute. • Temperature normal range is from 36.5ºC to 37.5ºC.
8. Normal laboratory results within normal range or with clinically non-significant deviation including: Complete Blood Count, Clinical Chemistry: Random blood sugar, blood urea, creatinine, sodium, potassium, total bilirubin, alanine amino transferase (ALT/GPT), aspartate amino transferase (AST/GOT), alkaline phosphatase, total protein in serum, Lipid profile, urinalysis.
9. Negative Virology tests: HIV (HIV Ab), hepatitis B (HBsAg), hepatitis C (HCV IgG).
10. Negative results for abused drug analysis in urine (Amphetamine (AMP), Barbiturate (BAR), Benzodiazepine (BZO), Cannabinoid (THC), Cocaine, Opiates (Morphine (MOP), Tramadol (TRA)).
11. Understanding of the study and agreeing to give a written informed consent.
12. Using an adequate contraception method during the study and for at least 30 days after the study (for potential subjects).

Exclusion Criteria:

1. Subjects who have atopic constitution, asthma or known allergy for the API under investigation and/or any other ingredients of the investigational product. 2. Presence of clinical relevance of cardiovascular, neurological, musculoskeletal, hematological, hepatic, gastrointestinal, renal, pulmonary, endocrinological, metabolism or psychiatric disease.

3. Symptomatic or asymptomatic orthostatic hypotension at screening defined by a decrease of SBP more than 20 mmHg or DBP more than 10 mmHg occurs between sitting/supine to standing position. The subject will be excluded (if the drug under investigation has antihypertensive properties or documented to have orthostatic hypotension as a side effect).

4. Presence or history of malabsorption or any gastrointestinal surgery except appendectomy or herniotomy.

5. Subjects who have given more than 400 mL blood within the last two months before the first drug administration and subjects who have participated in any drug research within the last two months before the first day of drug administration.

6. Subjects who used any prescribed systemic medication (including OTC medication) within 2 weeks (or six elimination half-lives of this medication, whichever is longer) before the initiation of the study (except for single doses of analgesics which have no drug interaction with study product).

7. Use of any vitamins or herbal products within 3 days prior to the initial dose of the study medication.

8. Subjects who have any chronic disease which might interfere with the absorption, distribution, metabolism or excretion of the drug.

9. Subjects who consumed grapefruit or grapefruit juice during 48 hr prior to drug administration, during the study.

10. History of alcohol abuse and/or regular use of more than 2 units of alcohol per day or positive alcohol test.

11. History of difficulty of swallowing. 12. Intake of enzyme-inducing, organ toxic, long half-life drugs within 4 weeks before start of the study 13. Subjects who follow a special diet due to any reason, e.g., vegetarian. 14. Has a recent acute infection. 15. Pregnant females or female subjects who practice lactation or unprotected females with pregnancy potential