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

内容摘要

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. 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. 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. The liver transplant recipients were stratified into a VRC co-therapy group (n&#x2009;=&#x2009;33) and a non-VRC control group (n&#x2009;=&#x2009;106). TAC dose-corrected trough concentrations (C0/D) were analyzed in relation to donor and recipient genotypes of CYP3A4*1G (rs2242480), CYP3A5*3 (rs776746), CYP2C19*2 (rs4244285), and CYP2C19*3 (rs4986893). During VRC co-therapy, dual donor-recipient CYP3A4*1G CC carriers exhibited a 73% increase in TAC C0/D compared with TT/TC genotypes (6.83 vs 3.95, p&#x2009;=&#x2009;0.0031). Recipients grafted from CYP3A5 non-expresser donors exhibited 34% higher TAC C0/D than those from CYP3A5 expressers (6.35 vs 4.75, p&#x2009;=&#x2009;0.0196). Recipient CYP2C19 poor metabolizers demonstrated 36% elevated TAC C0/D compared to extensive or intermediate metabolizers (6.47 vs 4.76, p&#x2009;=&#x2009;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 C0/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 C0/D remained significantly elevated for 5&#x2009;days before returning to baseline level by day 6 (p&#x2009;<&#x2009;0.0001). 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. Donor and recipient genes jointly determine the risk of drug interaction between tacrolimus and voriconazole after liver transplant Why was the study done? For patients who have received a liver transplant, finding the right dose of the anti-rejection drug Tacrolimus (TAC) is crucial. Another drug, Voriconazole (VRC), used to prevent fungal infections, is known to strongly increase TAC levels in the blood, raising the risk of overexposure and toxicity. While a patient&#x2019;s own genes can affect how they process drugs, the role of the donor&#x2019;s liver genes in this specific drug interaction has been unclear. What did the researchers do? The researchers followed 139 liver transplant patients receiving TAC (Of these, 33 patients also received VRC). They investigated how the genes involved in drug metabolism (CYP3A4, CYP3A5, and CYP2C19) of both the organ donor and the recipient influences TAC blood levels when the two drugs (TAC and VRC) are used together after a liver transplant. What did the researchers find? When both the donor and the recipient carried a specific gene type (CYP3A4*1G CC), TAC levels were 73% higher compared to other gene combinations. Livers from donors with a CYP3A5*3 GG gene type led to 34% higher TAC levels in recipients than livers from donors with a CYP3A5*3 AA or CYP3A5*3 AG gene type. Recipients who were CYP2C19 poor metabolizers had 36% higher TAC levels than extensive or intermediate metabolizers. After VRC was discontinued, TAC levels remained significantly elevated for 5&#x2009;days and returned to baseline by the 6th day. What do the findings mean? Using genetic information from both the donor and the recipient could help doctors personalize TAC dosing more accurately when TAC and VRC are used together in liver transplant patients, improving safety and effectiveness. When stopping VRC therapy, it may be safer to wait until at least the 6th day before adjusting the TAC dose back up, to prevent accidental overexposure.