Advagraf (Adv), a prolonged release formulation of tacrolimus (tac), allows once-a-day administration and improves medication adherence.
Patients (pts) possessing at least one CYP3A5*1 allele have an increased tac metabolism.This prospective study evaluates the clinical interest of a new simplified starting-dose protocol of Adv after renal transplantation (RT) according to recipient CYP3A5 polymorphism.
Material and method
CYP3A5 genotype (CYP3A5*1/*1, CYP3A5*1/*3, CYP3A5*3/*3) was determined at the time of HLA typing. All pts received one 0.1 mg/kg of Adv prior to RT. On day 1, the Adv dose was adapted according to CYP3A5 genotype: 0.35 and 0.30 mg/kg/d in CYP3A5*1/*1 and CYP3A5*1/*3 respectively. CYP3A5 non expressors (CYP3A5*3/*3) were stratified to receive either 0.20 (control group) or 0.25 mg/kg/day. The daily dose (dd) remained unchanged for the first 3 days. The first tac trough level (TL) was determined at day 3 and the first dose adaptation made on day 4. Associated therapy included MMF and CS. Pts requiring plasma exchange because of prior sensitization were excluded.
Results: From January 2011 to July 2012, 84 consecutive pts (mean age: 48±21 ys ,53M/31F) were included. Median Follow up (FU) was12 mo (3-21).
In the12 pts expressing CYP3A5 (two*1/*1, ten*1/*3), the dd needed to achieve a similar tac TLs to CYP3A5*3/*3 remained significantly higher throughout the entire FU.
|Time post TR||CYP3A5||Day 8||Day 14||Mo 1||Mo 3||Mo 6||1 year|
|Mean Adv dd(mg/kg/d)||*1/||0,34***||0,35***||0,34***||0,27***||0,26***||0,22*|
|Mean Tac TL (ng/ml)||*1/||11*||10,5**||12,2||9||8,8||7,3|
|Mean MDRD (ml/min)||*1/||56||53||57||57||62||74|
Among pts CYP3A5 non expressors (n:72), 34 and 38 received a starting Adv dose of 0.2 and 0.25 mg/k/d respectively. After dose adaptation intended to reach a comparable tac TLs in both groups, we observed a significantly higher infratherapeutic tac TL rate in the control group (p<0.02).
Conclusion: Use of Adv de novo after RT is effective when CYP3A5 polymorphism is taken into account. CYP3A5 expressors require a higher dd. In CYP3A5*3/*3 pts, a higher starting dose than that currently recommended is also advisable to avoid infratherapeutic TL that increases the risk of acute rejection.
To cite this abstract in AMA style:Meyer MDe, Haufroid V, Kanaan N, Pauw LDe, Eddour DChaib, Mourad M. Influence of Recipient Cytochrome P450 3A5 Polymorphism on the Metabolism of Advagraf Administered De Novo after Renal Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/influence-of-recipient-cytochrome-p450-3a5-polymorphism-on-the-metabolism-of-advagraf-administered-de-novo-after-renal-transplantation/. Accessed June 3, 2020.
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