CYTOCHROME P4503A5 AND TNF–a GENOTYPES ARE ASSOCIATED WITH TACROLIMUS DOSING IN PEDIATRIC HEART TRANSPLANT PATIENTS

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TITLE: CYTOCHROME P4503A5 AND TNF–a GENOTYPES ARE ASSOCIATED WITH TACROLIMUS DOSING IN PEDIATRIC HEART TRANSPLANT PATIENTS

H. X. Zheng,¹ S. Webber,³ E. Schuetz,⁴ A. Zeevi,² J. Lamba,⁴ J. Zhang,⁴ P. Bowman,³ G. Burckart.¹

¹Pharmaceutical Sciences, University of Pittsburgh; ²Pathology, University of Pittsburgh; ³Children Hospital, University of Pittsburgh; ⁴Pharmaceutical Sciences, St.Jude Children’s Research Hospital

Tacrolimus (Tac), a substrate for cytochrome (CYP) P4503A, is a potent immunosuppressive agent used in organ transplantation. TNF–a is a cytokine that has been shown affect both acute rejection and CYP450 drug metabolism. The objective of this study was to examine the influence of CYP3A5 and TNF–a genotypes on Tac dosing in pediatric heart transplant (HTx) patients. Methods: 77 pediatric HTx patients were studied. Tac blood level (ng/ml) per dose (mg/kg/day) at 3 and 12 months post HTx was calculated as [L/D]. CYP3A5*1 (expressor) and CYP 3A5*3 (non–expressor) genotypes were determined by PCR amplification and direct sequencing. TNF–a (–308) genotyping was performed using the PCR–SSP technique (One Lamda commercial kit). Comparisons were performed using Student`s T test. Results: At 3 months, a significant difference in Tac [L/D] was found between the CYP3A5 expressor vs non–expressor genotypes (30.5 vs. 58.0, p = 0.037). This difference was also observed at 12 months (36.3 vs. 64.1, p = 0.05). Although TNF–a genotype had no direct effect on [L/D] alone, its combination with the CYP3A5 genotype enhanced the prediction of Tac [L/D]. The Tac [L/D] was significantly lower in patients with the combination of TNF–a high (GA/AA) and CYP3A5 expressor genotypes than those with the combination of TNF–a low (GG) and CYP3A5 non–expressor genotype (16.0 vs. 59.5, p = 0.001 at 3 month, 26.4 vs. 68.1, p = 0.02 at 12 month). Discussion: Tac dosing in organ transplant patients should be related to CYP3A function. We have previously shown that TNF–a genotype was related to acute rejection in this patient population. The interaction of the TNF–a high/low genotype with CYP3A5 genotype/phenotype demonstrates the influence of endogenous substrates on drug disposition. We conclude that (1) a low [L/D] (a higher dose per level) for Tac in pediatric HTx patients is associated with the CYP3A5 expressor genotypes, and (2) the TNF–a genotype enhances this CYP3A5 influence on Tac dosing.