Influence of genetic polymorphisms of CYP3A5 and ABCB1 on sirolimus pharmacokinetics, patient and graft survival and other clinical outcomes in renal transplant.

Abstract

In transplant patients receiving de novo anticalcineurin-free sirolimus (SRL)-based immunosuppression, we determined the influence of cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette, sub-family B (MDR/TAP), member (ABCB1) genotypes on SRL blood levels and medium-term relevant clinical outcomes, in order to improve effectiveness of immunosuppression strategies when anti-mammalian target of rapamycin (anti-mTOR) inhibitor is indicated for clinical reasons. Forty-eight renal transplant recipients (suffered 48% diabetes mellitus, 91% hypertension, and 47% dyslipidemia) were genotyped for CYP3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Sirolimus blood levels were determined using microparticle enzyme immunoassay technique. Relationships between genotypes and pharmacokinetics, graft function, and patient-graft survival were determined by univariate analysis. CYP3A5*1/*3 showed lower SRL levels than CYP3A5*3/*3 (4.13±1.54 vs. 8.49±4.18 ng/mL; p=0.003) and level/dose ratio (LDR) (92.74±37.47 vs. 178.62±116.45; p=0.019) in early post-transplant period. In ABCB1 polymorphisms, CT genotypes showed higher SRL levels than CC and TT (8.93±2.22 vs. 7.28±2.47 vs. 7.35±1.15 ng/mL; p=0.038) in the late period; LDR in CC and CT were 171.29±36.24 vs. 335.66±138.71 (p=0.003), despite receiving lower doses (p=0.018). Acute rejection rate was 14% vs. 42% for *3/*3 and 14% (TT), 48% (CT), and 31% (CC). Median patient survival was 45 months, significantly lower than that of *3/*3 patients (69 months). Death-censored graft survival during 5-year follow-up was similar for both CYP3A5 genotypes and significantly lower in TT than CT and CC groups, without survival differences. CYP3A5 and ABCB1 polymorphisms influenced SRL levels; preliminary data suggest this may affect patient and graft survival. Genotyping renal transplant patients could help select candidates for SRL (genotype*3/*3 for CYP3A5 and CT for ABCB1), when anti-mTOR immunosuppression is indicated.