Evaluation of Everolimus Pharmacokinetic Monitoring Based on Trough Concentration and Area Under the Blood Concentration Time Curve in Kidney Transplantation

Backgrounds Everolimus (EVR) is an mTOR inhibitor used in kidney transplantation to minimize calcineurin inhibitor exposure. Although therapeutic drug monitoring (TDM) based on trough concentrations (C0) is standard, the relationship between time-point EVR concentrations, systemic exposure, and metabolic complications of tacrolimus (TAC)-based therapy remains unclear. This study aimed to identify the optimal sampling point that reflects systemic exposure and to evaluate its association with adverse effects. Methods We analyzed 827 pharmacokinetic assessments of 168 kidney transplant recipients who received TAC-based immunosuppression. EVR concentrations were measured at 0 (C0), 1, 2, 3, and 4 hours post-dose, and the area under the concentration–time curve from 0 to 4 hours (AUC₀–₄) was calculated. Correlations between each time point and the AUC₀–₄ were evaluated, and logistic regression adjusted for TAC trough concentration was used to assess the associations between EVR exposure and adverse events, including proteinuria and de novo hyperlipidemia (HL). Results The median participant age was 50 years, and 39.3% of participants were female. Among all time points, C2 showed the strongest correlation with the AUC₀–₄ (r = 0.944, p < 0.001), whereas C0 showed only a moderate association (r = 0.524, p < 0.001). Time-course analysis revealed that peak the concentration typically occurred 2 hours post-dose, although the profiles varied according to the post-transplant duration. EVR AUC₀–₄ was independently and positively associated with the development of de novo HL (adjusted OR 1.02, p = 0.03), whereas higher TAC trough concentrations exhibited a protective effect (adjusted OR 0.84, p = 0.01), suggesting that TAC co-administration may modulate EVR-induced lipid dysregulation. No significant relationship was observed between EVR exposure and proteinuria. Receiver operating characteristic analysis yielded an AUC of 0.603 with an optimal cutoff of 39.9 ng·h/mL for predicting HL. Conclusions C2 most accurately reflected systemic EVR exposure under tacrolimus-based regimens. Higher EVR exposure, as represented by AUC₀–₄ or C2, was associated with an increased risk of de novo hyperlipidemia, whereas higher TAC levels mitigated this effect. These findings support the clinical utility of C2- or AUC-based TDM for individualized EVR dosing to balance the efficacy and safety in kidney transplant recipients. Clinical trial number Not applicable.