Single Dose Crossover Comparative Bioavailability Study of Two Formulations of Fluconazole 200 mg in Healthy Adult Subjects Under Fasting Conditions

NCT04038008 | Completed Phase 1

• 1 other identifier: PTL-P3-438 (v. 1.0 2019/07/12)
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This single dose study is designed in accordance with EMA (the European Medicines Agency) regulatory guidelines, with the aim of characterizing the comparative bioavailability of fluconazole in the two formulations in healthy subjects. As this is a bioequivalence trial where each subject will receive each study treatment in a crossover fashion, a control group is not included. Within the clinical portion of the study each subject will receive a single oral dose of the test and the reference formulation in compliance with the generated randomization code. The primary study endpoints are the pharmacokinetic (PK) parameters Cmax and AUC0-t of fluconazole.

Conditions

Bioequivalence

Keywords

fluconazole; Diflucan®; bioequivalence

Outcome Measures

Primary Outcomes (3)

• Maximum observed concentration (Cmax) of fluconazole in plasma after administration of the test and the reference products

  Maximum observed concentration in plasma

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

• AUC0-T of fluconazole in plasma after administration of the test and the reference products

  Cumulative area under the concentration time curve calculated from 0 to TLQC using the linear trapezoidal method, where TLQC represents time of last observed quantifiable concentration

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

• AUC0-72 of fluconazole in plasma after administration of the test and the reference products (in case if AUC0-T is less than 80% of AUC0-∞ in more than 20% of the observations, truncated AUC0-72 will be used as primary endpoint instead of AUC0-T)

  Cumulative area under the concentration time curve calculated from 0 to 72 hours using the linear trapezoidal method. Nominal time will be used to estimate AUC0-72 using the NCA built-in tool in Phoenix® WinNonlin®. Any actual time that deviates by more than 1 minute from the 72-hour time point will be extrapolated/intrapolated as per Phoenix® WinNonlin®'s built-in formulas.

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

Secondary Outcomes (8)

• Tmax of fluconazole in plasma after administration of the test and the reference products

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

• TLQC of fluconazole in plasma after administration of the test and the reference products

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

• AUC0-∞ of fluconazole in plasma after administration of the test and the reference products

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

• Residual area of fluconazole in plasma after administration of the test and the reference products

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

• Time point where the log-linear elimination phase begins (TLIN) of fluconazole in plasma after administration of the test and the reference products

  0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration

Study Arms (2)

Sequence AB

OTHER

13 subjects assigned to the sequence AB will receive a single 200 mg dose of test product Fluconazole (1 x 200 mg tablet), marked as A in the sequence, in Period 1 and a single 200 mg dose of reference product Diflucan® (1 x 200 mg hard capsule), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet or hard capsule must be swallowed whole and must not be chewed or broken.

Drug: Fluconazole; Drug: Diflucan®

Sequence BA

OTHER

13 subjects assigned to the sequence BA will receive a single 200 mg dose of reference product Diflucan® (1 x 200 mg hard capsule), marked as B in the sequence, in Period 1 and test product Fluconazole (1 x 200 mg tablet), marked as A in the sequence, in Period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet or hard capsule must be swallowed whole and must not be chewed or broken.

Drug: Fluconazole; Drug: Diflucan®

Interventions

Fluconazole DRUG

Fluconazole is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 200 mg of fluconazole.

Also known as: Test Product

Sequence AB; Sequence BA

Diflucan® DRUG

Diflucan® is manufactured by Fareva Amboise, France (MAH: PFIZER PHARMA PFE GmbH, Germany). Each hard capsule contains 200 mg of fluconazole.

Also known as: Reference Product

Sequence AB; Sequence BA

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated informed consent form (ICF)
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Healthy Caucasian adult male or female
• If female, meets one of the following criteria:
• Is of childbearing potential and agrees to use one of the accepted contraceptive regimens from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug. An acceptable method of contraception includes one of the following:
• Abstinence from heterosexual intercourse
• Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
• Intrauterine device (with or without hormones)
• Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository)
• Male partner vasectomized at least 6 months prior to the first study drug administration
• Male partner has had a vasectomy less than 6 months prior to dosing, and agrees to use an additional acceptable contraceptive method from the first study drug administration through to at least 30 days after the last dose of the study drug
• Is of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a postmenopausal state (i.e. at least 1 year without menses without an alternative medical condition prior to the first study drug administration)
• Aged at least 18 years but not older than 55 years
• Body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively
• Non- or ex-smoker (An ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration)

You may not qualify if:

• Female who is lactating at screening
• Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration
• History of significant hypersensitivity to fluconazole, any related azole compounds, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs
• Presence or history of significant gastrointestinal, liver or kidney disease, or any other condition that is known to interfere with drug absorption, distribution, metabolism or excretion, or known to potentiate or predispose to undesired effects
• History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease
• Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment
• Seated blood pressure below 110/60 mmHg at the screening visit
• History of rare hereditary problems of galactose and/or lactose intolerance, lactase deficiency or glucose-galactose malabsorption
• Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
• Any clinically significant illness in the 28 days prior to the first study drug administration
• Use of any prescription drugs (with the exception of hormonal contraceptives or hormone replacement therapy) in the 28 days prior to the first study drug administration, that in the opinion of an investigator would put into question the status of the participant as healthy
• Any history of tuberculosis
• Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration
• Positive screening results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HBsAG (B) (hepatitis B)) or Hepatitis C Virus (HCV (C)) tests
• Intake of fluconazole in the 28 days prior to the first study drug administration

Sponsors & Collaborators

• Pharmtechnology LLC: lead
• Altasciences Company Inc.: collaborator

Study Sites (1)

Altasciences Company Inc.

Mount Royal, Quebec, H3P 3P1, Canada

Location

MeSH Terms

Interventions

Fluconazole

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Eric Sicard, MD

  Altasciences Company Inc.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The randomization code will not be available to the personnel of the bioanalytical facility until the bioanalytical tables have been finalized and audited by the Quality Assurance (QA) department.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2019
• First Posted: July 30, 2019
• Study Start: July 26, 2019
• Primary Completion: September 17, 2019
• Study Completion: January 13, 2020
• Last Updated: November 30, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)