Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients

Abstract

Tacrolimus exhibits inter-patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P-glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race-adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race-adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical, and genomic factors in stable black and white renal transplant recipients. A secondary objective investigated race-based tacrolimus regimens and genotype-specific dosing. Sixty-seven recipients receiving oral tacrolimus and mycophenolic acid ≥6 months completed a 12-hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236C>T, 2677G>T/A, 3435C>T polymorphisms were characterized. Patients were classified as extensive, intermediate, and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with computer software (NONMEM 7.3, ICON Development Solutions; Ellicott City, Maryland). A 2-compartment model with first-order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P value < .05), which was faster in extensive (mean: 45.0 L/hr) and intermediate (29.5 L/hr) metabolizers than poor metabolizers (19.8 L/hr). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between black and white recipients with different CYP3A5 genotypes.

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

“…15,16 CYP3A5*6 (rs10264272) and *7 (rs413003343) are reduced or loss-of-function variants which are observed exclusively in individuals of African ancestry. [23][24][25] Identifying the influential variants in each population is important in developing accurate precision medicine dose models for tacrolimus, therefore we previously conducted genome-wide association studies (GWAS) of tacrolimus troughs in kidney transplant recipients of European and African ancestry to identify ancestry-specific genetic variants. [18][19][20][21][22] We have shown in our work that up to 50% of variability in tacrolimus pharmacokinetic is explained by CYP3A genetic variants and clinical factors.…”

“…[18][19][20][21][22] We have shown in our work that up to 50% of variability in tacrolimus pharmacokinetic is explained by CYP3A genetic variants and clinical factors. [23][24][25] Identifying the influential variants in each population is important in developing accurate precision medicine dose models for tacrolimus, therefore we previously conducted genome-wide association studies (GWAS) of tacrolimus troughs in kidney transplant recipients of European and African ancestry to identify ancestry-specific genetic variants. 24,25 The evidence for the association between genetic variation and tacrolimus disposition is strong and a Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline provides recommendations on tacrolimus directed dosing using the CYP3A5*3, *6, and *7 variants.…”

The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients

“…The study was conducted at the UB Renal Research Unit at the Erie County Medical Center. Study design and methods have been previously described . Clinical stability was based on physical examination, comprehensive metabolic panel, fasting lipid panel and complete blood count at enrolment and on study morning.…”

“…A metabolic composite CYP3A5*3*6*7 was generated based upon the combined allelic status for each single‐nucleotide polymorphism (SNP). Patients were classified as extensive, intermediate and poor CYP3A5*3*6*7 metabolizers .…”

“…The first aim of this study is to investigate whether standardized extrarenal AEs are associated with tacrolimus exposure metrics, generated using a previously published population pharmacokinetic model , in stable renal transplant recipients. The second aim is to develop a LSS to enable therapeutic drug monitoring strategies in the clinic using model‐predicted tacrolimus exposure metrics.…”