Influence of Recipient Cytochrome P450 3A5 Polymorphism on the Metabolism of Advagraf Administered De Novo after Renal Transplantation
Abdominal Surgery and Transplantation, Cliniques Universitaires St Luc UCL, Brussels, Belgium
Biochemistry,
Nephrology,
Meeting: 2013 American Transplant Congress
Abstract number: 214
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 |
| N pts | *1/ | 12 | 12 | 12 | 12 | 11 | 7 |
| *3/*3 | 72 | 72 | 72 | 72 | 58 | 38 | |
| Mean Adv dd(mg/kg/d) | *1/ | 0,34*** | 0,35*** | 0,34*** | 0,27*** | 0,26*** | 0,22* |
| *3/*3 | 0,20 | 0,19 | 0,17 | 0,11 | 0,09 | 0,09 | |
| Mean Tac TL (ng/ml) | *1/ | 11* | 10,5** | 12,2 | 9 | 8,8 | 7,3 |
| *3/*3 | 14,3 | 13,4 | 13,4 | 9 | 7,8 | 6,9 | |
| Mean MDRD (ml/min) | *1/ | 56 | 53 | 57 | 57 | 62 | 74 |
| *3/*3 | 37 | 37 | 46 | 51 | 55 | 60 |
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 November 23, 2024.« Back to 2013 American Transplant Congress