Clinical trial NCT01388387: Pharmacogenetic Study of Tacrolimus in Hepatic Transplant (CYPTAC'H)
Official title: Impact of Donor and Recipient CYP3A5 Genetic Polymorphism on Tacrolimus Exposure in Patients With Hepatic Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hepatic Transplantation
Keywords: pharmacogenetics
pharmacokinetics
tacrolimus
genetic polymorphism
CYP3A5
liver transplantation
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2011-07-06
Enrollment: 154
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The choice of an immunosuppressant after hepatic transplant is now more difficult than before because of the increasing number of drugs available.

Pharmacokinetic, pharmacodynamic and pharmacogenetic information can help to choose the best treatment and the best dose for each patient. The genetic polymorphism of enzymes metabolizing treatments can affect their efficacy and safety. Concerning tacrolimus, CYP3A5 activity is a major determinant of the dose needed to reach target concentrations. This study is aimed at evaluating the impact of both donor and recipient CYP3A5 genetic polymorphisms on tacrolimus exposure in patients with hepatic transplant.

Detailed description: Pharmacogenetics is a recent tool which could help to choose the best immunosuppressive therapy in patients with hepatic transplant. Indeed, the CYP3A5 gene has many polymorphisms and one of them, g.6986 A\>G, is the major determinant of the variability of expression of this protein. The allele \*1 (g6986A) leads to normal protein expression while the allele \*3 (g.6986G) causes lack of protein expression, and their different combinations induce a great variability in tacrolimus concentrations. As cytochromes are present in the liver and intestine, in hepatic transplant, tacrolimus exposure results from both recipient (enterocytes) and donor (liver) enzymes. Recent studies demonstrated a significant role of the genotype recipient on the dose/concentration relationship and on the dose needed to reach target concentrations. However, these studies were insufficient to analyze more precisely all impacts of this polymorphism because they did not include enough patients. The purpose of the investigators study is to evaluate the impact of donor and recipient CYP3A5 genetic polymorphism on tacrolimus exposure in patients with hepatic transplant after the first administration of tacrolimus and at 7 days post transplantation, when the dose has been adapted to avoid too high blood levels and to limit serious adverse reactions.

Eligibility criteria: Inclusion Criteria:

* Adults (\>18 years) of Caucasian origin,
* with hepatic transplant,
* who are going to be treated by tacrolimus, and
* who gave free, well-informed and written consent.

Non-inclusion Criteria:

* Participation to another protocol incompatible with the study,
* HIV patients with antiretroviral treatment,
* Patients with legal guardianship or deprived of freedom.

Primary outcomes:
measure: Exposure to tacrolimus after the first administration, using tacrolimus area under curve (AUC) between 0 and 12 hours, weighted by the dose administered.
timeFrame: 12 hours
Secondary outcomes:
measure: Pharmacokinetics after the first administration and after 7 days of treatment
timeFrame: 7 days
measure: Clinical follow-up during the 3 months post transplantation
timeFrame: 3 months
Other outcomes:
Locations:
city: Rennes
country: France
facility: Service des Maladies du Foie - Hôpital de Pontchaillou
Study officials:
affiliation: Rennes University Hospital
name: Eric BELLISSANT, MD, PhD
role: STUDY_CHAIR
affiliation: Rennes University Hospital
name: Marie-Clémence VERDIER, PharmD
role: STUDY_CHAIR
References:
citation: Tron C, Woillard JB, Houssel-Debry P, David V, Jezequel C, Rayar M, Balakirouchenane D, Blanchet B, Debord J, Petitcollin A, Roussel M, Verdier MC, Bellissant E, Lemaitre F. Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients. PLoS One. 2020 Mar 12;15(3):e0230195. doi: 10.1371/journal.pone.0230195. eCollection 2020.