Tacrolimus Pharmacokinetics in Young, Middle Age and Older Renal Transplant Recipients- Impact of CYP3A5*3*6*7 Metabolic Composite
1University at Buffalo
School of Pharmacy, Buffalo, NY, 2Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 3Marshall University
School of Medicine, Huntington, WV, 4University at Buffalo
School of Medicine, Buffalo, NY
Meeting: 2019 American Transplant Congress
Abstract number: 395
Keywords: Age factors, Gene polymorphism, Immunosuppression, Kidney transplantation
Session Information
Session Name: Concurrent Session: Non-Organ Specific: Pharmacogenomics / Pharmacokinetics
Session Type: Concurrent Session
Date: Monday, June 3, 2019
Session Time: 4:30pm-6:00pm
Presentation Time: 4:54pm-5:06pm
Location: Room 210
*Purpose: In spite of increased renal transplantation in patients over 60 years and the need for age-adjusted tacrolimus maintenance immunosuppression, limited pharmacokinetic comparisons between young, middle age and elderly renal transplant recipients(RTR) have been reported. Interpatient variability in tacrolimus pharmacokinetics is due primarily to metabolism by cytochrome P-450 3A5(CYP3A5) isoenzymes and is attributed to CYP3A5 single nucleotide polymorphisms(SNP). This sub-study investigated the impact of adult age on tacrolimus pharmacokinetics in stable RTR with the influence of CYP3A5*3*6*7 metabolic composite.
*Methods: The 12-hour pharmacokinetic study of tacrolimus was investigated in 67 stable RTR receiving enteric coated mycophenolic acid and tacrolimus. Patents were categorized by age as follows: Young: >21 & ≤ 40 years; Middle Age: >40 &≤ 60 years and Elderly>60 years. Apparent clearance (CL) normalized to BMI (CL/BMI), Area Under the Concentration-time curve 0-12h (AUC0-12), and 0 hour troughs (C-0h) were determined. The CYP3A5 polymorphisms:*3[rs776746],*6[10264272],*7[41303343], associated with loss of protein function were characterized and used as a covariate to describe extensive, intermediate and poor metabolism. Univariate ANOVA was conducted using SAS V 9.4.
*Results: Table 1 summarizes the results. All group means were within the therapeutic AUC0-12 guide of 120-200 mg.hr/ml for tacrolimus. The elderly received the lowest tacrolimus dose and achieved comparable, therapeutic troughs with a trend toward a lower CL/BMI [pair-wise comparison between middle and older ages; P=0.058].CYP3A5*3*6*7 metabolic composite was a significant covariate (P<0.001) and accounted for 31% of the variability in CL/BMI.
*Conclusions: These findings warrant further investigation into tacrolimus pharmacokinetics to guide individualized regimens based upon age, CYP3A5*3*6*7 metabolic composite and clinical responses to achieve safe and efficacious drug exposures (i.e. AUC0-12).
| Endpoints | Young(n=16) | Middle Age(n=38) | Elderly(n=13) | P Value |
| e-GFR | 57.0 (16.0) | 53.0(14.3) | 59.4 (19.3) | 0.390 |
| TAC Dose(mg) | 3.3(1.4) | 3.6(1.9) | 2.7 (1.6) | 0.257 |
| C-0h (ng/ml) | 6.8(1.6) | 6.9(1.9) | 6.7(1.7) | 0.948 |
| AUC0-12 (ng.hr/ml) | 126.0(31.1) | 124.6(33.8) | 126.7(31.4) | 0.976 |
| CL/BMI | 1.01 (0.51) | 1.01(0.51) | 0.68(0.38) | 0.055+ |
To cite this abstract in AMA style:
Tornatore K, Attwood K, Brazeau D, Venuto R. Tacrolimus Pharmacokinetics in Young, Middle Age and Older Renal Transplant Recipients- Impact of CYP3A5*3*6*7 Metabolic Composite [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/tacrolimus-pharmacokinetics-in-young-middle-age-and-older-renal-transplant-recipients-impact-of-cyp3a5367-metabolic-composite/. Accessed November 22, 2024.« Back to 2019 American Transplant Congress