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