Discordance between trough concentration and tacrolimus exposure on the day of kidney transplantation: a prospective pharmacokinetic study

Tacrolimus trough concentration (C0) serves as a surrogate for drug exposure, but perioperative factors may disrupt this relationship early post-transplantation. We assessed whether the morning trough concentration (C0) on the day of kidney transplantation (POD0) accurately reflects 12-h tacrolimus exposure compared with a relatively stable early reference (POD7). We then derived the POD0 C0 corresponding to the same exposure as the conventional POD7 reference (a C0 of 7–9 ng/mL). We prospectively enrolled 80 de novo kidney transplant recipients receiving immediate-release tacrolimus and performed intensive pharmacokinetic sampling on POD0 (C0, C2, C3, C4, C10) and POD7 (C0, C2, C8). Dose-time-anchored AUC0-12 was calculated using the linear trapezoidal rule. The POD0 C0 corresponding to the POD7 reference AUC0-12 was derived by inverting linear, power, and median quantile regression models. Despite only a modest difference in morning C0 values (POD0 median 7.15 vs. POD7 6.40 ng/mL), the POD0 AUC0-12 was substantially higher than that on POD7 (138.9 vs. 105.4 ng·h/mL, p < 0.001); after adjustment for trough concentration, this difference was attenuated but remained significant (approximately +18% at a matched C0). Additionally, the C0–AUC slope on POD0 was approximately 30% lower than on POD7 (12.0 vs. 17.1 per 1 ng/mL). The POD7 reference AUC (125 [IQR 112–144] ng·h/mL at C0 7–9 ng/mL) corresponded on POD0 to a C0 of approximately 6.8 ng/mL (the robust quantile estimate; 5.5–6.8 ng/mL across the three models). Trough C0 levels underestimated tacrolimus exposure on the day of kidney transplantation. On POD0, a trough of approximately 6–8 ng/mL corresponded to an AUC0-12 at or above this relatively stable early reference. These findings are hypothesis-generating and indicate that troughs need not be driven high early to achieve adequate exposure.