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Donor and recipient genetic polymorphisms modulate tacrolimus pharmacokinetics during voriconazole co-therapy: a drug–drug interaction study in liver transplant recipients

Year: 2026

Type: article

Abstract: Background: While recipient cytochrome P450 (CYP) genetic polymorphisms are established modulators of tacrolimus (TAC) pharmacokinetics, the combined effects of donor-derived hepatic and recipient intestinal CYP3A4/5 and CYP2C19 genotypes during voriconazole (VRC)-mediated CYP3A inhibition remain inadequately elucidated in liver transplantation. Objectives: This study evaluated the impact of donor and recipient CYP3A4/5 and CYP2C19 polymorphisms on TAC pharmacokinetics during VRC co-therapy in liver transplant recipients. Design: A retrospective study was conducted on 139 liver transplant patients receiving TAC-based immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2025. Methods: The liver transplant recipients were stratified into a VRC co-therapy group ( n = 33) and a non-VRC control group ( n = 106). TAC dose-corrected trough concentrations (C 0 /D) were analyzed in relation to donor and recipient genotypes of CYP3A4*1G (rs2242480), CYP3A5*3 (rs776746), CYP2C19*2 (rs4244285), and CYP2C19*3 (rs4986893). Results: During VRC co-therapy, dual donor-recipient CYP3A4*1G CC carriers exhibited a 73% increase in TAC C 0 /D compared with TT/TC genotypes (6.83 vs 3.95, p = 0.0031). Recipients grafted from CYP3A5 non-expresser donors exhibited 34% higher TAC C 0 /D than those from CYP3A5 expressers (6.35 vs 4.75, p = 0.0196). Recipient CYP2C19 poor metabolizers demonstrated 36% elevated TAC C 0 /D compared to extensive or intermediate metabolizers (6.47 vs 4.76, p = 0.0401). The magnitude of TAC-VRC interaction was modulated by both donor and recipient genotypes. Comparing with the control group, VRC co-therapy increased TAC C 0 /D by 3.80- and 2.75-fold increases in CYP3A5 expresser and non-expresser recipients, respectively, and by 3.44- and 3.53-fold in recipients grafted from CYP3A5 expresser and non-expresser donors, respectively. Post-VRC discontinuation, TAC C 0 /D remained significantly elevated for 5 days before returning to baseline level by day 6 ( p < 0.0001). Conclusion: In summary, Donor and recipient CYP3A4/5 and CYP2C19 genotypes jointly influence TAC pharmacokinetics during VRC co-therapy. Genotype-guided dosing strategies integrating both donor and recipient genotypes may improve TAC dosing precision. TAC dose reinstatement may be deferred until day six following VRC discontinuation to avoid overexposure.

Source: Therapeutic Advances in Drug Safety

DOI: 10.1177/20420986261420282