A Bioequivalence Study of Losartan Potassium Tablets (Containing Losartan Potassium 100 mg) in Normal, Healthy, Adults Under Fasting Conditions

A Randomized, Open-label, Single-dose, Two-treatment, Two-sequence, Two-period, Crossover Bioequivalence Study of Test Losartan Potassium Tablets (Containing Losartan Potassium 100 mg) of Pharmtechnology LLC, Republic of Belarus With Reference Cozaar® (Containing Losartan Potassium 100 mg) of "Merck Sharpe & Dohme B.V.", Haarlem, the Netherlands in Normal, Healthy, Adult, Human Subjects Under Fasting Conditions

To demonstrate bioequivalence of single dose test formulation of Losartan potassium tablets (containing Losartan potassium 100 mg) of Pharmtechnology LLC, Republic of Belarus with reference Cozaar® (containing Losartan potassium 100 mg) of "Merck Sharpe & Dohme B.V.", Haarlem, the Netherlands in normal, healthy, adult, human subjects under fasting conditions.To monitor adverse events and ensure the safety

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Losartan potassium 100mg; Drug: Cozaar 100mg Tablet

Detailed Description

Total 66 normal healthy adult subjects will be enrolled in the study. Subjects will be administered either the Test or the Reference Product with 200 mL of water in each period as per the randomization schedule. Subjects will fast for at least 10 hours prior to administration of the study drugs and for four (4) hours after administration of the study drugs during each study period. Standardized meals will be provided in each study period. Water will not be accessible to the subjects 1 hour to administration of the study drugs and 1 hour after administration of the study drugs in each period. A total of 29 blood samples will be withdrawn for pharmacokinetic profiling during each study period. The plasma concentrations of losartan and its carboxylic acid metabolite will be measured by a validated LC-MS/MS analytical method. ANOVA will be performed on log transformed pharmacokinetic parameters Cmax, AUC0-t, AUC0-∞, and 90% confidence interval will be constructed for the ratio of geometric least square mean of the Test and Reference products, obtained from the log-transformed data. Bioequivalence will be concluded if the ratio estimate as well as its 90% confidence interval, both falls within the acceptable range of 80.00% to 125.00% for Cmax, AUC0-t.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• India
  • Maharashtra
    • Mumbai, Maharashtra, India, 400 701
      • Clinical Unit, Reliance Life Sciences Pvt. Ltd.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

The following criteria should be checked at the time of study entry. If any does not apply at the time of study entry, the subject must not be included in the study:

1. Healthy adult human subjects, aged between 18 to 45 years (both inclusive).
2. Subjects with Body Mass Index (BMI) 18.5 to 24.9 kg/m2
3. Subjects able and willing to comply with the protocol requirements.
4. Subjects should not have any medical history of significant diseases.

5. If subject is a female and is

   • of child bearing potential, she should be practicing an acceptable method of birth control for the duration of the study as suggested by the investigator, such as a combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier method), intrauterine device (IUD), or abstinence.

   OR

   • surgically sterile, bilateral tubal ligation done at least 6 months before the study should be documented.
6. Subjects willing to voluntarily provide written informed consent.
7. Subjects willing to undergo pre- and post-study physical examinations and laboratory investigations.
8. Subjects who are non-smokers based on history.

9. Subjects willing to adhere to the protocol and the following study requirements:

   • Should not consume xanthine containing products, such as coffee, tea, chocolate or soft drinks at least 48 hours prior to dosing (i.e. in-house monitoring and the remaining based on history) until the last sample collection.
   • Should not consume alcohol at least 48 hours prior to dosing (i.e. during in-house monitoring and the remaining based on history) until the last sample collection.
   • Should not consume grapefruit or its products at least 7 days prior to each dosing (i.e. during in-house monitoring and the remaining based on history) and until the last sample collection.
10. Subjects having no clinically significant medical history and no clinically significant abnormalities in general physical examination, laboratory assessments, 12-lead ECG, chest X-Ray or vital signs.

Exclusion Criteria:

The following criteria should be checked at the time of study entry. If any of these apply at the time of study entry, the subject must not be included in the study:

1. Subjects incapable of understanding the informed consent process.
2. Female subjects with a positive pregnancy test at screening or positive serum β-HCG test (done at check-in of each study periods) or lactating females.
3. Female subjects of childbearing potential who are unwilling or unable to use an appropriate method of contraception as outlined in the inclusion criteria, at least 28 days prior to the first period dosing until the post-study follow-up (i.e. until 7 days from the drug administration in Period II). Use of hormonal contraceptives either oral or implants within 3 months prior to first period dosing will not be acceptable.
4. Subjects with inadequate venous access in their left or right arm to allow the collection of all samples via venous cannula in the study.
5. Subjects with abnormalities in resting heart rate (>100 beats/min or <50 beats/min), blood pressure either hypotensive episode (systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg) or hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥90 mmHg), oral temperature (< 95.60F or > 990F) on the screening day.
6. Subjects with history of psychiatric disorders, which are likely to limit the validity of consent to participate in the study, or limit the ability to comply with the protocol requirements.
7. Subjects with any evidence of organ dysfunction or any clinically significant deviation from normal in their physical or clinical evaluation including ECG and X-ray results.
8. Subjects who have taken over the counter or prescribed medications, including any enzyme modifying drugs or any systemic medication within 30 days prior to the start of the clinical period and during the study period.
9. Subjects with a known history of drug hypersensitivity to losartan or any excipients of the formulation.
10. Subjects with a history of alcohol abuse and/or drug abuse or who are found urinary screen test positive for drugs of abuse (Amphetamines, Morphine, Benzodiazepines, Marijuana, Cocaine and Barbiturates) or are found with current alcohol abuse based on alcohol breath test.
11. Subjects diagnosed to be HIV 1 and 2 or Hepatitis B (HBsAg) or Hepatitis C (HCV) virus positive.
12. Subjects with clinically significant abnormal haematological values [haemoglobin (Hb), total white blood cells count (WBC), total red blood cells count (RBC), differential WBC count, platelet count and hematocrit].
13. Subjects with clinically significant abnormal laboratory values for serum creatinine, blood urea nitrogen (BUN), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum alkaline phosphatase (ALP), serum bilirubin, serum glucose (fasting), and serum cholesterol.
14. Subjects with clinically significant abnormal urine analysis, defined as the presence of RBC (>5/HPF), pus cells (>5/HPF), epithelial cells (>5/HPF), glucose (positive), ketones (positive), bilirubin (positive) and protein (positive) (unless the clinical investigator considers the deviation to be irrelevant for the purpose of the study).

15. Subjects with a clinically significant past history or current medical condition of:

    1. Pulmonary disorders (COPD and asthma)
    2. Cardiovascular disorders (especially heart blocks, myocardial infarction, congestive heart failure and uncontrolled hypertension)
    3. Neurological disorders (especially epileptic seizures)
    4. GIT disorders (gastrointestinal bleeding, gastric/peptic ulcer)
    5. Renal and/or hepatic disorders
    6. Coagulation disorders
    7. Endocrine disorders (especially diabetes mellitus)
16. Any history of difficulty in donating blood
17. Any clinically significant illness during 3 months before screening.
18. Subjects who participated in any other clinical investigation using experimental drugs or have bled more than 300 mL in the past 3 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Losartan potassium 100 mg Tablets; Losartan potassium is the test product. In period 1 and period 2, 33 of 66 subjects will be given single oral dose (1 x 100 mg) of Losartan potassium.	Drug: Losartan potassium 100mg; Losartan potassium 100 mg Tablets ( Pharmtechnology LLC, Republic of Belarus)
Active Comparator: Cozaar® (Losartan potassium)100 mg Tablets; Cozaar® (Losartan potassium) is the reference product. In period 1 and period 2, 33 of 66 subjects will be given single oral dose (1 x 100 mg) of Cozaar®.	Drug: Cozaar 100mg Tablet; Cozaar® ( Losartan potassium) 100 mg Tablets(Merck Sharpe & Dohme B.V. , Haarlem, the Netherlands)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameter for losartan	Peak Plasma Concentration (Cmax)	10 Days
Pharmacokinetic parameter for losartan	Area under the plasma concentration versus time curve from time 0 to the last measured concentration (AUC0-t)	10 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of investigational products	Number of adverse events, number of deaths, number of severe adverse events in subjects who have taken at least one dose of investigational products.	17 Days
Other pharmacokinetic parameters for losartan	Area under the plasma concentration versus time curve from time 0 to to infinite time(AUC0-∞)	10 Days
Other pharmacokinetic parameters for losartan	Time of maximum measured plasma concentration (Tmax)	10 Days
Other pharmacokinetic parameters for losartan	Elimination or terminal half-life (T1/2)	10 Days
Other pharmacokinetic parameters for losartan	Elimination rate constant (Kel)	10 Days
Other pharmacokinetic parameters for losartan	Residual area (AUCresid)	10 Days

Collaborators and Investigators

• Sponsor: Pharmtechnology LLC
• Collaborators: Reliance Life Sciences Private Limited
• Investigators: Principal Investigator: Suresh A Maroli, MD, Reliance Life Sciences Pvt. Ltd

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2018
• Primary Completion (Actual): March 11, 2018
• Study Completion (Actual): March 16, 2018

Study Registration Dates

• First Submitted: February 27, 2018
• First Submitted That Met QC Criteria: March 3, 2018
• First Posted (Actual): March 9, 2018

Study Record Updates

• Last Update Posted (Actual): November 2, 2018
• Last Update Submitted That Met QC Criteria: October 31, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Bioequivalence
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: RLS/1117/046

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: The Company may provide the individual participant data after privacy protection on case by case basis.

Drug and device information, study documents

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