Bioequivalence Study of Two Formulations of Perindopril 4 mg Tablet Under Fasting Condition

Overview

The objective of this study was to find out whether the bioavailability of PT Dexa Medica's formulation of 4 mg perindopril tert-butylamine tablets was equivalent to that of the innovator's product (Prexum® 4 mg, Servier).

Full Title of Study: “Bioequivalence Study of 4 mg Perindopril Tablets Produced by PT Dexa Medica in Comparison With the Reference Tablets (Prexum® 4 mg, Servier)Under Fasting Condition”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Investigator)
  • Study Primary Completion Date: November 2008

Detailed Description

The participating subjects were required to have an overnight fast and in the next morning were given orally one tablet of the test drug (Perindopril 4 mg tablets of PT Dexa Medica) or one tablet of the reference drug (Prexum® 4 mg, Servier).

Blood samples were drawn immediately before taking the drug (control), and at 20, 40 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, 192 hours after drug administration.

Three weeks after the first drug administration (washout period), the procedure was repeated using the alternate drug.

The pharmacokinetic parameters, including AUCt, AUCinf, Cmax, t max, and t1/2, were determined based on the concentrations of the perindopril parent compound and the metabolite perindoprilat, using high-performance liquid chromatography method with tandem mass spectrometry detector (LC-MS/MS).

Interventions

  • Drug: Perindopril 4 mg tablets of PT Dexa Medica
    • Test product was given as a single dose, under the procedure as described in the Section: Detailed description of the study.
  • Drug: Perindopril 4 mg tablets of Servier
    • Reference product was given as a single dose, under the procedure as described in the Section: Detailed description of the study.

Arms, Groups and Cohorts

  • Experimental: Perindopril 4 mg tablets of PT Dexa Medica
    • Group I (Test product): each tablet contains perindopril tert-butylamine salt 4 mg. A single dose of perindopril tablet of PT Dexa Medica was given to each of study subjects.
  • Active Comparator: Perindopril 4 mg tablets of Servier
    • Group II (Reference product) : each tablet contains perindopril tert-butylamine salt 4 mg. A single dose of perindopril (Prexum) tablets of Servier was given to each of study subjects.

Clinical Trial Outcome Measures

Primary Measures

  • Area under concentration-time curve (AUC)of perindopril parent compound
    • Time Frame: 192 hours
    • Relative bioavailability (primarily measured by AUCt and AUCinf) between two perindopril 4 mg tablet formulations (test and reference formulations) under fasting condition. The AUC was measured based on the plasma concentration of perindopril parent compound.
  • Area under concentration-time curve (AUC)of perindoprilat
    • Time Frame: 192 hours
    • Relative bioavailability (primarily measured by AUCt and AUCinf) between two perindopril 4 mg tablet formulations (test and reference formulations) under fasting condition. The AUC was measured based on the plasma concentration of the active metabolite, perindoprilat.

Secondary Measures

  • Peak plasma concentration (Cmax)of perindopril parent compound
    • Time Frame: 192 hours
    • Relative bioavailability (secondarily measured by Cmax) between two perindopril 4 mg tablet formulations (test and reference formulations) under fasting condition. The Cmax was measured based on the plasma concentration of perindopril parent compound.
  • Peak plasma concentration (Cmax)of perindoprilat
    • Time Frame: 192 hours
    • Relative bioavailability (secondarily measured by Cmax) between two perindopril 4 mg tablet formulations (test and reference formulations) under fasting condition. The Cmax was measured based on the plasma concentration of the active metabolite, perindoprilat.
  • Time to achieve the peak plasma concentration (tmax)of perindopril parent compound
    • Time Frame: 192 hours
  • Time to achieve the peak plasma concentration (tmax)of perindoprilat
    • Time Frame: 192 hours
  • Elimination half-life (t1/2)of perindopril parent compound
    • Time Frame: 192 hours
  • Elimination half-life (t1/2)of perindoprilat
    • Time Frame: 192 hours

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy male and female subjects
  • Aged 18-55 years inclusive
  • A body mass index in the range of 18-25 kg/m2
  • Able to participate, communicate well with the investigators and willing to give informed consent
  • Non-smokers
  • Vital signs (after 10 minutes resting) are within the following ranges:
  • systolic blood pressure 100-125 mmHg
  • diastolic blood pressure 60-80 mmHg
  • pulse rate 60-90 bpm

Exclusion Criteria

  • Pregnant or lactating women
  • Known hypersensitivity or contraindication to perindopril
  • Intake of any prescription drug within 14 days of this study's first dosing day
  • Intake of any non-prescription drug, food supplement, or herbal medicine within 7 days of this study's first dosing day
  • History or presence of any liver dysfunction (ALT, alkaline phosphatase, total bilirubin ≥ 1.5 ULN)
  • History of any bleeding or coagulation disorders
  • Clinically significant ECG abnormalities
  • Clinically significant haematology abnormalities
  • Renal insufficiency (plasma creatinine concentration ≥ 1.4 mg/dL)
  • Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of the study drug
  • A donation or loss of 500 mL (or more) of blood within 3 months before this study's first dosing day
  • A positive hepatitis B surface antigen (HBsAg), anti-HCV, and anti-HIV
  • History of drug or alcohol abuse within 12 months prior to screening of this study
  • Participation in a previous study within 3 months of this study's first dosing day

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Dexa Medica Group
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Danang A Yunaidi, MD, Principal Investigator, PT. Equilab International

References

Bellissant E, Giudicelli JF. Pharmacokinetic-pharmacodynamic model for perindoprilat regional haemodynamic effects in healthy volunteers and in congestive heart failure patients. Br J Clin Pharmacol. 2001 Jul;52(1):25-33.

Louis WJ, Workman BS, Conway EL, Worland P, Rowley K, Drummer O, McNeil JJ, Harris G, Jarrott B. Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects. J Cardiovasc Pharmacol. 1992 Sep;20(3):505-11.

Sennesael J, Ali A, Sweny P, Vandenburg M, Slovic D, Dratwa M, Resplandy G, Genissel P, Desche P. The pharmacokinetics of perindopril and its effects on serum angiotensin converting enzyme activity in hypertensive patients with chronic renal failure. Br J Clin Pharmacol. 1992 Jan;33(1):93-9.

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