Beyond Single Nucleotide Polymorphisms: CYP3A5∗3∗6∗7 Composite and ABCB1 Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients.

Daniel A Brazeau,Kathleen M Tornatore,Joseph D Consiglio,Kristopher Attwood,Gregory E Wilding,Calvin J Meaney,Rocco C Venuto,Aijaz Gundroo,Shirley S Chang,Louise Cooper

doi:10.3389/fgene.2020.00889

Abstract

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both CYP3A5 or ABCB1. Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both CYP3A5 and ABCB1. A metabolic composite based upon the CYP3A5 polymorphisms: ∗3(rs776746), ∗6(10264272), and ∗7(41303343), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of ABCB1 on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: 1236C > T (rs1128503), 2677G > T/A(rs2032582), and 3435C > T(rs1045642). Finally, a combined analysis using both CYP3A5 and ABCB1 polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three CYP3A5 loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance (P < 0.001) with 50% lower AUC∗ (P < 0.001) than Poor metabolizers. No differences in C12 h were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The ABCB1 haplotype analysis detected significant associations of the wildtype 1236T-2677T-3435T haplotype to tacrolimus dose (P = 0.03), CL (P = 0.023), CL/LBW (P = 0.022), and AUC∗ (P = 0.078). Finally, analysis combining CYP3A5 and ABCB1 genotypes indicated that the presence of the ABCB1 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite CYP3A5∗3∗4∗5 and ABCB1 haplotypes. Consideration of multiple alleles using CYP3A5 metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.

Highlights

The combination of tacrolimus and mycophenolic acid is the mainstay of maintenance immunosuppressive regimens to prevent renal allograft rejection (Hart et al, 2017; Jouve et al, 2018)
P-glycoprotein interacts with gastrointestinal and hepatic cytochrome P450 3A isoenzymes to modulate tacrolimus pharmacokinetics which impacts systemic and cellular drug distribution (Fan et al, 2010; Hesselink et al, 2014; Shuker et al, 2016b). Both ABCB1 and Cytochrome P-450 3A5 isoenzymes (CYP3A5) variants play an essential role in modulation of intracellular tacrolimus concentrations (Kim et al, 2001; Fredericks et al, 2006; Cattaneo et al, 2009; Hesselink et al, 2014) and overall systematic tacrolimus exposure
We present a pharmacogenetic analysis employing a CYP3A5∗3∗6∗7 composite and ABCB1 haplotypes to clinically identify rapid versus poor metabolizers of tacrolimus

Summary

Introduction

The combination of tacrolimus and mycophenolic acid is the mainstay of maintenance immunosuppressive regimens to prevent renal allograft rejection (Hart et al, 2017; Jouve et al, 2018). Tacrolimus exhibits variable pharmacokinetics and clinical response, necessitating the use of therapeutic drug monitoring (TDM) (Schiff et al, 2007; de Jonge et al, 2009; Shuker et al, 2015, 2016b; Vanhove et al, 2016). The duration of chronic renal allograft survival in Blacks is significantly shorter compared to other races receiving similar immunosuppression (Young and Gaston, 2000, 2002, 2005; Young and Kew, 2005; Eckhoff et al, 2007; Fan et al, 2010; Andrews et al, 2016). Contributing factors include socioeconomics, genomic variants, medication adherence, pharmacokinetic and pharmacodynamic variability, donorrecipient mismatches, time on dialysis and racial variation in immunodynamic responses (Young and Gaston, 2005; Young and Kew, 2005; Eckhoff et al, 2007; Page et al, 2012).

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