Pharmacokinetics and Monitoring of Methotrexate in Adults with Acute Lymphoblastic Leukaemia: A 10-Year Follow-Up at an Italian Centre

<b>Background</b>: High-dose methotrexate (HDMTX) is widely used for acute lymphoblastic leukaemia (ALL), but its pharmacokinetic (PK) variability and toxicity require therapeutic drug monitoring (TDM). Our 10-year retrospective study investigated HDMTX PK parameters and their associations with renal and hepatic biomarkers in an Italian cohort of adult patients with ALL. <b>Methods</b>: Plasma MTX concentrations [MTX C(p)] were measured at 24-, 48-, and 72 h post-infusion. PK modelling was performed to calculate area under the curve (AUC_{0 → 72 h}) and half-life (t½). Creatinine, total bilirubin, and sample quality indices were retrieved from routine clinical laboratory analyses. <b>Results</b>: Mean (±SEM) MTX plasma concentrations were 36.09 ± 15.53 μmol/L, 0.93 ± 0.43 μmol/L, and 0.30 ± 0.07 μmol/L at 24, 48, and 72 h, respectively, with marked inter-patient variability. PK analysis showed a mean AUC_{0 → 72 h} of 112.85 ± 34.09 h·μmol/L and a t½ of 17.15 ± 2.40 h. MTX C(p) and AUC_{0 → 72 h} showed significant positive correlations with serum creatinine at all time points, confirming renal function as a major MTX clearance determinant. Age moderated the relationship at 72 h, with younger patients showing stronger correlations. Hepatic function measured by total bilirubin also correlated with MTX C(p) and AUC_{0 → 72 h} at 48 and 72 h, especially in younger patients, suggesting a hepatic contribution to MTX variability. No associations were found between the PK parameters and lipemic, icterus, or haemolysis indices. <b>Conclusions</b>: These findings highlight the value of integrating renal and hepatic biomarkers into HDMTX drug monitoring protocols. Such biomarker-informed TDM may improve the safety and efficacy by identifying patients at risk of delayed clearance and toxicity, especially younger individuals or those with renal insufficiency.