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