CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients.
OBJECTIVE
Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5(*)3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation.


METHODS
A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5(*)3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C(0)) were measured on day 3 and 10, and month 1, 3, 6 and 12.


RESULTS
Compared with CYP3A5(*)3/(*)3 individuals (n=110), patients carrying at least one CYP3A5(*)1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C(0) on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C(0) were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36).


CONCLUSIONS
We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.
Hesselink
Dennis A
DA
Department of Internal Medicine, Renal Transplant Unit, Erasmus MC, Rotterdam, The Netherlands. d.a.hesselink@erasmusmc.nl
van Schaik
Ron H N
RH
van Agteren
Madelon
M
de Fijter
Johannes W
JW
Hartmann
Anders
A
Zeier
Martin
M
Budde
Klemens
K
Kuypers
Dirk R J
DR
Pisarski
Przemyslav
P
Le Meur
Yann
Y
Mamelok
Richard D
RD
van Gelder
Teun
T
D000208:Acute Disease; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D003404:Creatinine / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007390:International Agencies; D007674:Kidney Diseases / Q000628:therapy; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011446:Prospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000627:therapeutic use*
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D003404:Creatinine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009173:Mycophenolic Acid; D016559:Tacrolimus