1 Introduction
Tacrolimus (TAC) is the primary immunosuppressive agent for lung transplantation recipients.1Despite its clinical superiority, prescribing TAC is complicated by its high inter- and intra-individual variability and narrow therapeutic window. The optimal therapeutic range for TAC in lung transplant recipients has not yet been established,2 and even when the trough level (C0) falls within predefined range, there is still a risk of sub-therapeutic or supra-therapeutic fluctuations with each individual measurement, leading to under- or over- immunosuppression. Therefore, TAC intra-patient variability (IPV) has been proposed as a potential risk factor for adverse clinical outcomes. Previous studies have confirmed the correlation between high IPV and rejection, graft failure and mortality in kidney and liver transplantation; 3-6 however, limited research has been conducted in lung transplantation.7-9
Furthermore, conflicting evidence exists regarding the reference ranges of TAC C0 in lung transplant recipients. Some lung transplantation centers recommend target ranges of C0 to be 10–25 ng/mL within the first two weeks, 10–20 ng/mL for the subsequent 6–10 weeks, and 10–15 ng/mL thereafter,10 or 12–15 ng/mL during the first year, and lowered to 9–12 ng/ml thereafter. 11, 12 However, recent evidence suggests that these recommendations may need to be revised downwards due to an increased risk of acute kidney injury (AKI) associated with elevated C0 levels following lung transplantation, particularly when they exceeded 15 ng/mL.13,14 On the other hand, emerging data indicates a potential correlation between lower C0 and inferior outcomes. For instance, Ryu reported an increased risk of rejection when C0 was below 9 ng/mL at one month after lung transplantation, 15 while Gallagher found that lower C0 at 6–12 months post-transplantation was a significant risk factor for chronic lung allograft dysfunction (CLAD).7
Previous studies have also indicated that the combined effect of dose corrected concentration (C/D) and high IPV may exert a more pronounced influence on adverse allograft outcomes. However, this combined effect has only been observed in kidney transplant recipients thus far; therefore, it remains to be fully explored in the context of lung transplantation. 16, 17
The cytochrome P450 (CYP) 3A5 isoenzyme plays a crucial role in the metabolism of TAC. The presence of CYP3A5*3 (rs776746) mutation leads to reduced CYP3A5 activity, thereby influencing TAC concentration and dose requirement. However, at present, the association betweenCYP3A5 genotype and TAC IPV has not been definitely recognized and further validation is required. 18
Therefore, the primary aim of this study was to investigate and validate the impact of TAC C0 and IPV on clinical outcomes, including the development of DSA, CLAD, and mortality, with an objective to establish optimal TAC exposure values. Furthermore, we conducted an assessment on the synergistic effect of TAC C0 and IPV. Additionally, we examined how the CYP3A5 genotype influenced TAC exposure during different time periods following lung transplantation.
2 Materials and Methods