Evaluation of Everolimus Pharmacokinetic Monitoring Based on Trough Concentration and Area Under the Curve (AUC) in Kidney Transplantation

Background: Everolimus (EVR) is an immunosuppressant used in kidney transplantation, offering potential benefits including reduced nephrotoxicity from calcineurin inhibitors (CNIs) and antiviral/antitumor effects. Although therapeutic drug monitoring (TDM) based on trough levels is common, data on EVR pharmacokinetics and adverse events remain limited. Methods: We analyzed 838 pharmacokinetic data points from 171 kidney transplant recipients managed at the University of Osaka. EVR levels were measured at 0 (C0), 1, 2, 3, and 4 hours post-dose. Area under the concentration-time curve from 0 to 4 hours (AUC0-4) was calculated. We assessed correlations between EVR levels and AUC0-4 and evaluated associations with proteinuria and de novo hyperlipidemia (HL). Results: C0 moderately correlated with AUC0-4 (r = 0.524, p < 0.001), while C2 showed the strongest correlation (r = 0.944, p < 0.001). The timing of peak concentration varied: C1 was highest after 3 months post-transplant, whereas C3–C4 peaked within the first 3 months. AUC0-4 was not associated with proteinuria. However, patients who developed de novo HL had significantly higher AUC0-4 values compared to those who did not (28.2 vs. 24.5 ng×h/mL, p < 0.01). Receiver operating characteristics (ROC) analysis for HL prediction based on AUC0-4 showed an AUC of 0.603. Conclusion: While trough EVR levels showed a correlation with AUC0-4, C2 demonstrated a stronger correlation, indicating that it may more accurately reflect systemic exposure. Moreover, higher AUC0-4 was associated with hyperlipidemia, suggesting its potential as a predictive marker for EVR-related adverse effects in kidney transplant recipients.