Clinical trial NCT04489134: P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release
Official title: P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pharmacokinetics
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2020-07-28
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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

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.


Eligibility criteria: 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)

Primary outcomes:
measure: Area under the curve
timeFrame: Between 0 and 24 hours
Secondary outcomes:
measure: Cmax
timeFrame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
measure: Trough concentration
timeFrame: 24 hours
measure: Apparent clearance
timeFrame: 0-24 hours
measure: Half-life
timeFrame: 0-24 hours
measure: AUC
timeFrame: 0-24 hours
measure: Cmax
timeFrame: Cmax Advagraf: 2-3 hours, Cmax Envarsus: 6-8 hours
measure: Cmin
timeFrame: 24 hours
measure: CI/F
timeFrame: 0-24 hours
measure: T1/2
timeFrame: 0-24 hours
measure: ABCB1 genotypes
timeFrame: Day 0
measure: Others genotypes
timeFrame: Day 0
Other outcomes:
Locations:
city: Rennes
country: France
facility: CHU de Rennes
Study officials:
References: