Korean J Transplant.  2022 Nov;36(Supple 1):S198. 10.4285/ATW2022.F-3323.

Effects of cytochrome P450 3A5 (CYP3A5) on pharmacokinetic profiles of tacrolimus in Thai patients with liver transplantation

Affiliations
  • 1Department of Transplantation Surgery, Chulalongkorn University, Bangkok, Thailand
  • 2Department of Pharmacology, Chulalongkorn University, Bangkok, Thailand
  • 3Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Chulalongkorn University, Bangkok, Thailand

Abstract

Background
Tacrolimus, an immunosuppressant used in liver transplant patients, has narrow therapeutic index and large inter-individual pharmacokinetic variability, partly due to the pharmacogenetic variation in the main drug-metabolizing enzyme cytochrome P450 3A5 (CYP3A5) However, the contribution of the donor (D)s genetic variation in CYP3A5 to the pharmacokinet-ics of tacrolimus measured in recipients (R) is still inconclusive. Therefore, we investigated the full pharmacokinetic profiles of tacrolimus in Thai deceased donor liver transplantation according to recipients/donors (R/D) pharmacogenetics.
Methods
At 1-week posttransplantation, plasma tacrolimus concentrations were measured at 0, 2, 4, 6, 9, 12 and 24 hours post-dose in 19 recipients using a semiautomated enzyme immunoassay technique. Pharmacokinetics profiles were calculat-ed (WinNonlin, including time to maximum plasma concentration [Tmax; hour], maximum plasma concentration [Cmax; ng/mL], trough plasma concentration [Ctrough; ng/mL], area under the concentration-time curve at 0–24 hours [AUC 0–24; hr.ng/mL], half-life [T1/2; hour], volume of distribution [Vz/F; L], and clearance [CL/F; L/hr]). Genotypes of CYP3A5*3 was analyzed in both R and D. CYP3A5*1/*1 and *1/*3 were regarded as CYP3A5 expressors (E). CYP3A5*3/*3 were reported as non-expressors (NE).
Results
Patients were classified into four groups according to R/D CYP3A5 phenotypes: RE/DE, R-NE/DE, RE/D-NE, and R-NE/ D-NE. R-NE/D-NE had a significant increase in Cmax (21.9 [19.6–23.7] vs. 10.6 [5.5–14.0] ng/mL, P=0.034) and tacrolimus dose (0.06 [0.06–0.08] vs. 0.04 [0.06–0.06], P=0.032) compared to RE/D-NE. There were trends of increased AUC 0–24 and de-creased CL/F in D-NE regardless of recipient phenotypes (Table 1). No difference was observed in other parameters.
Conclusions
Genetic variation of CYP3A5 in donors affects overall drug accumulation and the clearance of tacrolimus in early posttransplant period. This suggested that the donors genetic variation should be considered in dose adjustment and therapeutic drug monitoring of tacrolimus. A prospective study with D/R genetic-guided treatment in a larger cohort is warranted.

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