P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release (DIPLOID)

December 10, 2024 updated by: Rennes University Hospital

Tacrolimus is a drug administered orally available with different formulations: immediate release (Prograf®), prolonged-release (Advagraf®) and an extended-release one named LCP-Tacro (Envarsus®), formulated using the Melt-Dose process.

Tacrolimus is a lipophilic macrolide drug able to passive transmembrane diffusion. Its bioavailability displays a large interindividual variability, from 9 to 43%. Indeed, tacrolimus is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). P-gp is an efflux protein mainly located at the apex of the epithelia of the intestine, lymphocyte, kidney and blood-brain barrier. P-gp therefore limits the intestinal resorption of tacrolimus and also its diffusion into its target compartment (i.e the lymphocyte. The expression of this protein is different throughout the digestive tract with maximum expression at the ileal level. CYP3A4 is a coenzyme that is responsible of more than 90% of the metabolism of tacrolimus, at the digestive and hepatic level. Both P-gp and CYP3A4 play a role in tacrolimus absorption/diffusion process.

A new formulation of tacrolimus, LCP-Tacro, (Envarsus®) was approved in 2014. Its efficacy was compared to Prograf® in two phase III de novo or switch Prograf® trials in kidney transplantation.

With tacrolimus, there is a strong inter-individual pharmacokinetic variability which, to date, has not been fully characterized. Variations in bioavailability may partly explain this high variability. The different formulations are resorbed at distinct gastrointestinal sites which could explain different absorptions between Prograf/Advagraf and LCP-Tacro forms.

These findings raise the question of the role of P-gp in explaining the difference in bioavailability between formulations. The use of a P-gp inhibitor could therefore have a different impact on exposure to different galenic formulations.

Verapamil is an inhibitor of P-gp and CYP 3A4, which is frequently prescribed and recommended by FDA for drug-drug interaction studies aiming at evaluating P-gp substrates, used in healthy volunteers at dosages up to 240 mg/D13-14. Otherwise, verapamil-tacrolimus interaction has been characterized in vitro.

It has also been shown that inhibitory effect of verapamil at a single dose of 120 mg administered one hour prior to the administration of a P-gp substrate exhibited an optimum power of inhibition.

The safety of Advagraf® and Envarsus® administrations have already been subjected to several phase I trials in healthy volunteers reinforcing the knowledge of their safety profile.

The aim of the study is to compare the interaction profile of Advagraf® and Envarsus® when co-administered with verapamil in healthy subjects and to provide guidelines on tacrolimus dosage adjustment in such cases.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
27

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • France
      • Rennes, France, 35055
        • CHU de Rennes

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • adults (> 18 years)
  • Non smokers (for at least 6 months)
  • Biological parameters within normal range (blood count, urea, creatinine, AST, ALT, GGT, bilirubine)
  • BMI within 18 and 25
  • Vaccinated against Covid 19
  • Negative urinary and plasma pregnancy test
  • Having effective contraception for the duration of the study and for 10 days after the last administration of the study treatment (for women and men of childbearing potential)
  • Informed consent

Exclusion Criteria:

  • participation to another study with incompatible procedure regarding the French law on research
  • Treatment with a drug drug interaction with tacrolimus
  • Cardiac rhythm at rest below 50 bpm
  • Cardiac issue detected on electrocardiogram
  • Cancer or history of cancer
  • Chronic infection or history of chronic infection
  • Diabetes or history of diabetes
  • Hypertension or history of hypertension
  • Pregnancy or lactation
  • Deprived of liberty (curatorship, guardianship or incarcerate)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: A D B C
Period n°01: Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°02:Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®) Period n°03:Administration of a 2 mg dose of LCP-tacro (Envarsus®) Period n°04:Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment A
Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment B
Administration of a 2 mg dose of LCP-tacro (Envarsus®)
Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)
Biological: Pharmacocinetik
Nine sampling points of 7 ml each will be taken on the first day at the CIC UIC and the last sampling point will be carried out at 24 hours from the administration the following morning.
Genetic: Genetic
A genetic analysis to determine your characteristics for enzymes in your metabolism as well as transport proteins will be carried out. An additional 7 ml blood tube will be drawn for this purpose during the first period.
Other: Selection visit:

During this visit, it will be asked to sign the following consent and it will be carried out:

  • a clinical examination (questioning and physical examination with measurement of height and weight);
  • a blood test (18 mL);
  • a blood pregnancy test if you are a woman;
  • a cardiac assessment (electrocardiogram).

These results should be normal.
Experimental: B A C D
Period n°01: Administration of a 2 mg dose of LCP-tacro (Envarsus®) Period n°02:Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°03:Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°04:Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)
Drug: Treatment A
Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment B
Administration of a 2 mg dose of LCP-tacro (Envarsus®)
Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)
Biological: Pharmacocinetik
Nine sampling points of 7 ml each will be taken on the first day at the CIC UIC and the last sampling point will be carried out at 24 hours from the administration the following morning.
Genetic: Genetic
A genetic analysis to determine your characteristics for enzymes in your metabolism as well as transport proteins will be carried out. An additional 7 ml blood tube will be drawn for this purpose during the first period.
Other: Selection visit:

During this visit, it will be asked to sign the following consent and it will be carried out:

  • a clinical examination (questioning and physical examination with measurement of height and weight);
  • a blood test (18 mL);
  • a blood pregnancy test if you are a woman;
  • a cardiac assessment (electrocardiogram).

These results should be normal.
Experimental: C B D A
Period n°01: Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°02:Administration of a 2 mg dose of LCP-tacro (Envarsus®) Period n°03:Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®) Period n°04:Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment A
Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment B
Administration of a 2 mg dose of LCP-tacro (Envarsus®)
Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)
Biological: Pharmacocinetik
Nine sampling points of 7 ml each will be taken on the first day at the CIC UIC and the last sampling point will be carried out at 24 hours from the administration the following morning.
Genetic: Genetic
A genetic analysis to determine your characteristics for enzymes in your metabolism as well as transport proteins will be carried out. An additional 7 ml blood tube will be drawn for this purpose during the first period.
Other: Selection visit:

During this visit, it will be asked to sign the following consent and it will be carried out:

  • a clinical examination (questioning and physical examination with measurement of height and weight);
  • a blood test (18 mL);
  • a blood pregnancy test if you are a woman;
  • a cardiac assessment (electrocardiogram).

These results should be normal.
Experimental: D C A B
Period n°01:Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®) Period n°02:Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°03:Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°04:Administration of a 2 mg dose of LCP-tacro (Envarsus®)
Drug: Treatment A
Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment B
Administration of a 2 mg dose of LCP-tacro (Envarsus®)
Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)
Biological: Pharmacocinetik
Nine sampling points of 7 ml each will be taken on the first day at the CIC UIC and the last sampling point will be carried out at 24 hours from the administration the following morning.
Genetic: Genetic
A genetic analysis to determine your characteristics for enzymes in your metabolism as well as transport proteins will be carried out. An additional 7 ml blood tube will be drawn for this purpose during the first period.
Other: Selection visit:

During this visit, it will be asked to sign the following consent and it will be carried out:

  • a clinical examination (questioning and physical examination with measurement of height and weight);
  • a blood test (18 mL);
  • a blood pregnancy test if you are a woman;
  • a cardiac assessment (electrocardiogram).

These results should be normal.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Area under the curve
Time Frame: Between 0 and 24 hours
Change in area under the curve of tacrolimus blood concentrations between 0 and 24h.
Between 0 and 24 hours

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Cmax
Time Frame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
Blood pharmacokinetic parameters: peak concentration (Cmax)
Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
Trough concentration
Time Frame: 24 hours
Blood pharmacokinetic parameters: trough concentration (Cmin)
24 hours
Apparent clearance
Time Frame: 0-24 hours
Blood pharmacokinetic parameters: apparent clearance (Cl/F)
0-24 hours
Half-life
Time Frame: 0-24 hours
Blood pharmacokinetic parameters: half-life (T1/2)).
0-24 hours
AUC
Time Frame: 0-24 hours
Intracellular pharmacokinetic parameters: AUC
0-24 hours
Cmax
Time Frame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
Intracellular pharmacokinetic parameters: Cmax
Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
Cmin
Time Frame: 24 hours
Intracellular pharmacokinetic parameters:Cmin
24 hours
CI/F
Time Frame: 0-24 hours
Intracellular pharmacokinetic parameters: Cl/F
0-24 hours
T1/2
Time Frame: 0-24 hours
Intracellular pharmacokinetic parameters:T1/2
0-24 hours
ABCB1 genotypes
Time Frame: Day 0
ABCB1 genotypes
Day 0
Others genotypes
Time Frame: Day 0
Other genotypes of interest coding for metabolism (CYP3A4, CYP3A5…) or drug transport (CNT3…).
Day 0

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Rennes University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 15, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 16, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 16, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 20, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 23, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 28, 2020

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 11, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 10, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2024

More Information

Terms related to this study

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 35RC19_8877_DIPLOID

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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