Clinical significance of personalized tacrolimus dosing by adjusting to donor CYP3A-status in liver transplant recipients

Abstract

Donor's CYP3A-status (CYP3A5 genotype and CYP3A4 expression) can provide prognostic information regarding tacrolimus-metabolizing capacity of the liver graft and initial tacrolimus dosing for therapeutic blood concentrations in liver transplants. The present work prospectively investigated whether CYP3A-status guided tacrolimus therapy has any potential clinical benefit for recipients in the early postoperative period.

Methods: The contribution of preliminary assaying of donor CYP3A-status to the optimization of initial tacrolimus therapy and to the reduction of adverse events (acute rejection, infection, nephrotoxicity) was investigated in 112 liver transplant recipients (CYPtest group) comparing to 101 control patients on tacrolimus concentration guided therapy.

Results: The time for achieving therapeutic tacrolimus concentration was significantly reduced, confirming potential benefit of initial tacrolimus therapy adjusted to donor's CYP3A-status over classical clinical practice of tacrolimus concentration guided treatment (4 vs 8 days, P < 0.0001). Acute rejection episodes (3.6 vs 23.8%, P < 0.0001) and tacrolimus induced nephrotoxicity (8 vs 27%, P = 0.0004) were less frequent in CYPtest group than in control patients, whereas occurrence of infectious disease was not influenced by tacrolimus dosing strategy (3.6 vs 5.9% in CYPtest and control groups, P > 0.05). Acute rejection was often accompanied with tacrolimus blood concentrations lower than 10 ng mL^-1 (20/24 of control and 2/4 of CYPtest patients), while nephrotoxicity was associated with high tacrolimus concentrations (>20 ng mL^-1 ) in the first week after transplantation (13/27 of control and 2/9 of CYPtest patients).

Conclusion: CYP3A-status guided therapy significantly improved the risk of misdosing induced early adverse effects (acute rejection, nephrotoxicity).

Keywords: CYP3A4 expression; CYP3A5 genotype; acute rejection; donor CYP3A-status; infection; liver transplant recipients; nephrotoxicity; tacrolimus.