<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04489134</url>
  </required_header>
  <id_info>
    <org_study_id>35RC19_8877_DIPLOID</org_study_id>
    <nct_id>NCT04489134</nct_id>
  </id_info>
  <brief_title>P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release</brief_title>
  <acronym>DIPLOID</acronym>
  <official_title>P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rennes University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rennes University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Tacrolimus is a drug administered orally available with different formulations: immediate&#xD;
      release (Prograf®), prolonged-release (Advagraf®) and an extended-release one named LCP-Tacro&#xD;
      (Envarsus®), formulated using the Melt-Dose process.&#xD;
&#xD;
      Tacrolimus is a lipophilic macrolide drug able to passive transmembrane diffusion. Its&#xD;
      bioavailability displays a large interindividual variability, from 9 to 43%. Indeed,&#xD;
      tacrolimus is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). P-gp is&#xD;
      an efflux protein mainly located at the apex of the epithelia of the intestine, lymphocyte,&#xD;
      kidney and blood-brain barrier. P-gp therefore limits the intestinal resorption of tacrolimus&#xD;
      and also its diffusion into its target compartment (i.e the lymphocyte. The expression of&#xD;
      this protein is different throughout the digestive tract with maximum expression at the ileal&#xD;
      level. CYP3A4 is a coenzyme that is responsible of more than 90% of the metabolism of&#xD;
      tacrolimus, at the digestive and hepatic level. Both P-gp and CYP3A4 play a role in&#xD;
      tacrolimus absorption/diffusion process.&#xD;
&#xD;
      A new formulation of tacrolimus, LCP-Tacro, (Envarsus®) was approved in 2014. Its efficacy&#xD;
      was compared to Prograf® in two phase III de novo or switch Prograf® trials in kidney&#xD;
      transplantation.&#xD;
&#xD;
      With tacrolimus, there is a strong inter-individual pharmacokinetic variability which, to&#xD;
      date, has not been fully characterized. Variations in bioavailability may partly explain this&#xD;
      high variability. The different formulations are resorbed at distinct gastrointestinal sites&#xD;
      which could explain different absorptions between Prograf/Advagraf and LCP-Tacro forms.&#xD;
&#xD;
      These findings raise the question of the role of P-gp in explaining the difference in&#xD;
      bioavailability between formulations. The use of a P-gp inhibitor could therefore have a&#xD;
      different impact on exposure to different galenic formulations.&#xD;
&#xD;
      Verapamil is an inhibitor of P-gp and CYP 3A4, which is frequently prescribed and recommended&#xD;
      by FDA for drug-drug interaction studies aiming at evaluating P-gp substrates, used in&#xD;
      healthy volunteers at dosages up to 240 mg/D13-14. Otherwise, verapamil-tacrolimus&#xD;
      interaction has been characterized in vitro.&#xD;
&#xD;
      It has also been shown that inhibitory effect of verapamil at a single dose of 120 mg&#xD;
      administered one hour prior to the administration of a P-gp substrate exhibited an optimum&#xD;
      power of inhibition.&#xD;
&#xD;
      The safety of Advagraf® and Envarsus® administrations have already been subjected to several&#xD;
      phase I trials in healthy volunteers reinforcing the knowledge of their safety profile.&#xD;
&#xD;
      The aim of the study is to compare the interaction profile of Advagraf® and Envarsus® when&#xD;
      co-administered with verapamil in healthy subjects and to provide guidelines on tacrolimus&#xD;
      dosage adjustment in such cases.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 15, 2022</start_date>
  <completion_date type="Anticipated">February 15, 2024</completion_date>
  <primary_completion_date type="Anticipated">February 15, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <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).</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>the biologists performing the tacrolimus assays will be blind to the treatment received</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the curve</measure>
    <time_frame>Between 0 and 24 hours</time_frame>
    <description>Change in area under the curve of tacrolimus blood concentrations between 0 and 24h.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cmax</measure>
    <time_frame>Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours</time_frame>
    <description>Blood pharmacokinetic parameters: peak concentration (Cmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trough concentration</measure>
    <time_frame>24 hours</time_frame>
    <description>Blood pharmacokinetic parameters: trough concentration (Cmin)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent clearance</measure>
    <time_frame>0-24 hours</time_frame>
    <description>Blood pharmacokinetic parameters: apparent clearance (Cl/F)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-life</measure>
    <time_frame>0-24 hours</time_frame>
    <description>Blood pharmacokinetic parameters: half-life (T1/2)).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC</measure>
    <time_frame>0-24 hours</time_frame>
    <description>Intracellular pharmacokinetic parameters: AUC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax</measure>
    <time_frame>Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours</time_frame>
    <description>Intracellular pharmacokinetic parameters: Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmin</measure>
    <time_frame>24 hours</time_frame>
    <description>Intracellular pharmacokinetic parameters:Cmin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CI/F</measure>
    <time_frame>0-24 hours</time_frame>
    <description>Intracellular pharmacokinetic parameters: Cl/F</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T1/2</measure>
    <time_frame>0-24 hours</time_frame>
    <description>Intracellular pharmacokinetic parameters:T1/2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ABCB1 genotypes</measure>
    <time_frame>Day 0</time_frame>
    <description>ABCB1 genotypes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Others genotypes</measure>
    <time_frame>Day 0</time_frame>
    <description>Other genotypes of interest coding for metabolism (CYP3A4, CYP3A5…) or drug transport (CNT3…).</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">28</enrollment>
  <condition>Pharmacokinetics</condition>
  <arm_group>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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®)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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®)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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®)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>D C A B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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®)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Treatment A</intervention_name>
    <description>Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)</description>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_label>D C A B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Treatment B</intervention_name>
    <description>Administration of a 2 mg dose of LCP-tacro (Envarsus®)</description>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_label>D C A B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Treament C</intervention_name>
    <description>Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)</description>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_label>D C A B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Treatment D</intervention_name>
    <description>Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)</description>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_label>D C A B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pharmacocinetik</intervention_name>
    <description>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.</description>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_label>D C A B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Genetic</intervention_name>
    <description>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.</description>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_label>D C A B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Selection visit:</intervention_name>
    <description>During this visit, it will be asked to sign the following consent and it will be carried out:&#xD;
a clinical examination (questioning and physical examination with measurement of height and weight);&#xD;
a blood test (18 mL);&#xD;
a blood pregnancy test if you are a woman;&#xD;
a cardiac assessment (electrocardiogram).&#xD;
These results should be normal.</description>
    <arm_group_label>A D B C</arm_group_label>
    <arm_group_label>B A C D</arm_group_label>
    <arm_group_label>C B D A</arm_group_label>
    <arm_group_label>D C A B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  adults (&gt; 18 years)&#xD;
&#xD;
          -  Non smokers (for at least 6 months)&#xD;
&#xD;
          -  Biological parameters within normal range (blood count, urea, creatinine, AST, ALT,&#xD;
             GGT, bilirubine)&#xD;
&#xD;
          -  BMI within 18 and 25&#xD;
&#xD;
          -  Vaccinated against Covid 19&#xD;
&#xD;
          -  Negative urinary and plasma pregnancy test&#xD;
&#xD;
          -  Having effective contraception for the duration of the study and for 10 days after the&#xD;
             last administration of the study treatment (for women and men of childbearing&#xD;
             potential)&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  participation to another study with incompatible procedure regarding the French law on&#xD;
             research&#xD;
&#xD;
          -  Treatment with a drug drug interaction with tacrolimus&#xD;
&#xD;
          -  Cardiac rhythm at rest below 50 bpm&#xD;
&#xD;
          -  Cardiac issue detected on electrocardiogram&#xD;
&#xD;
          -  Cancer or history of cancer&#xD;
&#xD;
          -  Chronic infection or history of chronic infection&#xD;
&#xD;
          -  Diabetes or history of diabetes&#xD;
&#xD;
          -  Hypertension or history of hypertension&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Deprived of liberty (curatorship, guardianship or incarcerate)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Marie LE NAOU</last_name>
    <phone>299282555</phone>
    <phone_ext>33</phone_ext>
    <email>marie.lenaou@chu-rennes.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Bruno Laviolle</last_name>
    <email>bruno.laviolle@chu-rennes.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>CHU de Rennes</name>
      <address>
        <city>Rennes</city>
        <zip>35055</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bruno Laviolle</last_name>
      <email>bruno.laviolle@chu-rennes.fr</email>
    </contact>
    <contact_backup>
      <last_name>Florian Lemaitre</last_name>
      <email>florian.lemaitre@chu-rennes.fr</email>
    </contact_backup>
    <investigator>
      <last_name>Fabrice Lainé</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Bruno Laviolle</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2020</study_first_posted>
  <last_update_submitted>March 15, 2022</last_update_submitted>
  <last_update_submitted_qc>March 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04489134
org study id: 35RC19_8877_DIPLOID
nct id: NCT04489134
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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).
primary purpose: Other
masking: Single (Outcomes Assessor)
masking description: the biologists performing the tacrolimus assays will be blind to the treatment received
measure: Area under the curve
time frame: Between 0 and 24 hours
description: Change in area under the curve of tacrolimus blood concentrations between 0 and 24h.
measure: Cmax
time frame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
description: Blood pharmacokinetic parameters: peak concentration (Cmax)
measure: Trough concentration
time frame: 24 hours
description: Blood pharmacokinetic parameters: trough concentration (Cmin)
measure: Apparent clearance
time frame: 0-24 hours
description: Blood pharmacokinetic parameters: apparent clearance (Cl/F)
measure: Half-life
time frame: 0-24 hours
description: Blood pharmacokinetic parameters: half-life (T1/2)).
measure: AUC
time frame: 0-24 hours
description: Intracellular pharmacokinetic parameters: AUC
measure: Cmax
time frame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
description: Intracellular pharmacokinetic parameters: Cmax
measure: Cmin
time frame: 24 hours
description: Intracellular pharmacokinetic parameters:Cmin
measure: CI/F
time frame: 0-24 hours
description: Intracellular pharmacokinetic parameters: Cl/F
measure: T1/2
time frame: 0-24 hours
description: Intracellular pharmacokinetic parameters:T1/2
measure: ABCB1 genotypes
time frame: Day 0
description: ABCB1 genotypes
measure: Others genotypes
time frame: Day 0
description: Other genotypes of interest coding for metabolism (CYP3A4, CYP3A5…) or drug transport (CNT3…).
arm group label: A D B C
arm group type: Experimental
description: 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®)
arm group label: B A C D
arm group type: Experimental
description: 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®)
arm group label: C B D A
arm group type: Experimental
description: 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®)
arm group label: D C A B
arm group type: Experimental
description: 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®)
intervention type: Drug
intervention name: Treatment A
description: Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
arm group label: A D B C
arm group label: B A C D
arm group label: C B D A
arm group label: D C A B
intervention type: Drug
intervention name: Treatment B
description: Administration of a 2 mg dose of LCP-tacro (Envarsus®)
arm group label: A D B C
arm group label: B A C D
arm group label: C B D A
arm group label: D C A B
intervention type: Drug
intervention name: Treament C
description: Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)
arm group label: A D B C
arm group label: B A C D
arm group label: C B D A
arm group label: D C A B
intervention type: Drug
intervention name: Treatment D
description: Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)
arm group label: A D B C
arm group label: B A C D
arm group label: C B D A
arm group label: D C A B
intervention type: Biological
intervention name: Pharmacocinetik
description: 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.
arm group label: A D B C
arm group label: B A C D
arm group label: C B D A
arm group label: D C A B
intervention type: Genetic
intervention name: Genetic
description: 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.
arm group label: A D B C
arm group label: B A C D
arm group label: C B D A
arm group label: D C A B
intervention type: Other
intervention name: Selection visit:
description: 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.
arm group label: A D B C
arm group label: B A C D
arm group label: C B D A
arm group label: D C A B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Marie LE NAOU
phone: 299282555
phone ext: 33
email: marie.lenaou@chu-rennes.fr
last name: Bruno Laviolle
email: bruno.laviolle@chu-rennes.fr
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: France
responsible party type: Sponsor