PK Assessment of Tacrolimus Exposure Before and After a Switch From Twice Daily Immediate-release (Prograf®) to Once-daily Prolonged Release Tacrolimus (Envarsus®) (ENVARSWITCH)

Pharmacokinetic Assessment of Tacrolimus Exposure Before and After a Switch From Twice Daily Immediate-release (Prograf®) to Once-daily Prolonged Release Tacrolimus (Envarsus®)

Tools have been developed in our unit to calculate the inter-dose AUC (Area Under Curve) of immunosuppressive drugs (ISD) based on a limited number of blood concentrations (i.e., blood samples) using Bayesian methods. Since 2005, we have implemented these tools in an expert system and made them available to the transplant community through our very successful ISBA (Immunosuppressive drugs Bayesian dose Adjustment) website.

Briefly, we first need to develop a population pharmacokinetic model using rich pharmacokinetic (PK) profiles (about 10 samples per patient over the dosing interval). The model developed can then be used for inference of ISD PK parameters in new patients using Bayesian estimation. Bayes' theorem is based on conditional probability: individual PK parameters are estimated based on the known PK parameters in the population (mean and distribution), given the dose and concentrations observed in a patient. Our previous studies have shown that a limited sampling strategy (LSS) based on 3 samples collected within the first 3 hours after drug intake can estimate adequately the interdose AUC of ISD. In the present study, the AUC0-24h and the recommended dose will be calculated using Bayesian estimators previously developed using PK data from the clinical trials run by Veloxis, and proposed to the clinicians via a dedicated website comparable with ISBA.

Study Overview

• Status: Unknown
• Conditions: Allograft
• Intervention / Treatment: Drug: switched from Prograf® to Envarsus®

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Pierre MARQUET, MD; Phone Number: +33 555 05 60 17; Email: pierre.marquet@unilim.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • University Hospital of Amiens
    • Contact: Gabriel CHOUKROUN, MD
  • Bordeaux, France
    • Recruiting
    • University Hospital of Bordeaux
    • Contact: Pierre MERVILLE, MD
  • Lille, France
    • Recruiting
    • University Hospital of Lille
    • Contact: Sébastien DHARANCY, MD
  • Limoges, France, 87 042
    • Recruiting
    • Limoges hospital
    • Contact: Pierre MARQUET, MD; Phone Number: +33 555 05 60 17; Email: pierre.marquet@unilim.fr
    • Principal Investigator: Marie ESSIG, MD
    • Principal Investigator: Marilyne DEBETTE-GRATIEN, MD
  • Paris, France
    • Recruiting
    • AP-HP
    • Contact: Dany ANGLICHEAU, MD
    • Principal Investigator: Christophe DUVOUX, MD
    • Principal Investigator: Faouzi SALIBA, MD
    • Principal Investigator: Filomena CONTI, MD
  • Poitiers, France
    • Recruiting
    • University Hospital of Poitiers
    • Contact: Antoine THIERRY, MD
  • Reims, France
    • Recruiting
    • University Hospital of Reims
    • Contact: Charlotte COLOSIO, MD
  • Rouen, France
    • Recruiting
    • University Hospital of Rouen
    • Contact: Isabelle ETIENNE, MD
  • Tours, France
    • Recruiting
    • University Hospital of Tours
    • Contact: Matthias BÜCHLER, MD
    • Principal Investigator: Ephrem SALAME, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult (≥ 18 year-old) male and female patients
2. Recipient of a single kidney or liver allograft
3. Patient transplanted for more than 2 weeks and less than 1 year at enrolment

4. Patient with stable Prograf® dose, defined by the following criteria:

   • Criterion 1: unchanged Prograf® dose for at least one week; if not, apply criterion #2
   • Criterion 2: unchanged Prograf® dose since the last two therapeutic drug monitorings (TDM)
5. Patient for whom the decision is made to switch from Prograf® to Envarsus®
6. Written informed consent obtained prior to any study-related procedure
7. Patient with tacrolimus C0 between 4 and 12 µg/L at V1
8. Patient with hematocrit > 27% at V1

Exclusion Criteria:

1. Patient presenting any contra-indication to tacrolimus according to the summary of product characteristics (SmPC) of Envarsus®
2. Recipient of any transplanted organ other than kidney or liver
3. Patient treated by Prograf® for less than 7 days at enrolment
4. Patient previously treated by any other investigational agent if it is not stopped at least 7 days prior to enrolment
5. Pregnant or lactating woman (based on declaration)
6. Patient under judicial protection
7. Patient incapable of understanding the purposes and risks of the study, who cannot give written informed consent, or who are unwilling to comply with the study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: DBS (dried blood spots) collection; In this study, we make a switch from Prograf® to Envarsus®. Patients will be trained to collect their blood from a finger prick on filter paper. DBS will be done at home, collected on filter paper and mailed by the patients to a centralized laboratory (Department of Pharmacology, Toxicology and Pharmacovigilance at Limoges University Hospital), where tacrolimus concentration will be determined by HPLC-MS/MS

Drug: switched from Prograf® to Envarsus®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference between the post-switch tacrolimus steady-state AUC0-24h (V4) and the pre-switch AUC0-24h (V2).	The tacrolimus AUC0-24h at V2 (patient on Prograf®) will be calculated by summing the morning and the evening tacrolimus AUC0-12h.	3 days

Collaborators and Investigators

• Sponsor: University Hospital, Limoges

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: August 19, 2016
• First Submitted That Met QC Criteria: August 24, 2016
• First Posted (Estimate): August 30, 2016

Study Record Updates

• Last Update Posted (Actual): May 23, 2019
• Last Update Submitted That Met QC Criteria: May 22, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: I160015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No