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

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ClinicalTrials.gov Identifier: NCT04489134
Recruitment Status : Not yet recruiting
First Posted : July 28, 2020
Last Update Posted : July 28, 2020
Sponsor:
Information provided by (Responsible Party):
Rennes University Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Pharmacokinetics Drug: Treatment A Drug: Treatment B Drug: Treament C Drug: Treatment D Biological: Pharmacocinetik Genetic: Genetic Other: Selection visit: Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: This is a pharmacokinetic, monocentric, prospective, randomized, crossover study with blind assessment (biologists performing tacrolimus dosages will be blind to the treatment received).
Masking: Single (Outcomes Assessor)
Masking Description: the biologists performing the tacrolimus assays will be blind to the treatment received
Primary Purpose: Other
Official Title: P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : May 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Arm Intervention/treatment
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 and a 2 mg dose of LCP-tacro Period n°03:Administration of a 2 mg dose of LCP-tacro Period n°04:Administration of a single 120 mg dose of immediate-release verapamil 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

Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)

Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil and a 2 mg dose of LCP-tacro

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 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 and a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°04:Administration of a single 120 mg dose of immediate release verapamil and a 2 mg dose of LCP-tacro
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

Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)

Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil and a 2 mg dose of LCP-tacro

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 and a 3 mg dose of prolonged-release tacrolimus (Advagraf®) Period n°02:Administration of a 2 mg dose of LCP-tacro Period n°03:Administration of a single 120 mg dose of immediate release verapamil and a 2 mg dose of LCP-tacro 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

Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)

Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil and a 2 mg dose of LCP-tacro

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 and a 2 mg dose of LCP-tacro Period n°02:Administration of a single 120 mg dose of immediate-release verapamil 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
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

Drug: Treament C
Administration of a single 120 mg dose of immediate-release verapamil and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)

Drug: Treatment D
Administration of a single 120 mg dose of immediate release verapamil and a 2 mg dose of LCP-tacro

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.





Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Cmax [ Time Frame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours ]
    Blood pharmacokinetic parameters: peak concentration (Cmax)

  2. Trough concentration [ Time Frame: 24 hours ]
    Blood pharmacokinetic parameters: trough concentration (Cmin)

  3. Apparent clearance [ Time Frame: 0-24 hours ]
    Blood pharmacokinetic parameters: apparent clearance (Cl/F)

  4. Half-life [ Time Frame: 0-24 hours ]
    Blood pharmacokinetic parameters: half-life (T1/2)).

  5. AUC [ Time Frame: 0-24 hours ]
    Intracellular pharmacokinetic parameters: AUC

  6. Cmax [ Time Frame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours ]
    Intracellular pharmacokinetic parameters: Cmax

  7. Cmin [ Time Frame: 24 hours ]
    Intracellular pharmacokinetic parameters:Cmin

  8. CI/F [ Time Frame: 0-24 hours ]
    Intracellular pharmacokinetic parameters: Cl/F

  9. T1/2 [ Time Frame: 0-24 hours ]
    Intracellular pharmacokinetic parameters:T1/2

  10. ABCB1 genotypes [ Time Frame: Day 0 ]
    ABCB1 genotypes

  11. Others genotypes [ Time Frame: Day 0 ]
    Other genotypes of interest coding for metabolism (CYP3A4, CYP3A5…) or drug transport (CNT3…).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • adults (> 18 years)
  • Non smokers
  • Biological parameters within normal range (blood count, urea, creatinine, AST, ALT, GGT, bilirubine)
  • BMI within 18 and 25
  • Negative urinary and plasma pregnancy test
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04489134


Contacts
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Contact: Marie LE NAOU 299282555 ext 33 marie.lenaou@chu-rennes.fr
Contact: Bruno Laviolle bruno.laviolle@chu-rennes.fr

Locations
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France
CHU de Rennes
Rennes, France, 35055
Contact: Bruno Laviolle       bruno.laviolle@chu-rennes.fr   
Contact: Florian Lemaitre       florian.lemaitre@chu-rennes.fr   
Sub-Investigator: Fabrice Lainé         
Principal Investigator: Bruno Laviolle         
Sponsors and Collaborators
Rennes University Hospital
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Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT04489134    
Other Study ID Numbers: 35RC19_8877_DIPLOID
First Posted: July 28, 2020    Key Record Dates
Last Update Posted: July 28, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No