Background: 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. Methods: 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 (AUC0 → 72 h) and half-life (t½). Creatinine, total bilirubin, and sample quality indices were retrieved from routine clinical laboratory analyses. Results: 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 AUC0 → 72 h of 112.85 ± 34.09 h·μmol/L and a t½ of 17.15 ± 2.40 h. MTX C(p) and AUC0 → 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 AUC0 → 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. Conclusions: 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.
Pharmacokinetics and Monitoring of Methotrexate in Adults with Acute Lymphoblastic Leukaemia: A 10-Year Follow-Up at an Italian Centre
Calabro, Pasquale FabioCo-primo
;Biso, LetiziaCo-primo
;Lastella, Marianna;Bandini, Arianna;Banchi, Marta;Tacchi, Costanza;Tang, Donghao;Carli, Marco;Fogli, Stefano;Paolicchi, Aldo;Scarselli, Marco;Di Paolo, Antonello;Bocci, Guido
Ultimo
2025-01-01
Abstract
Background: 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. Methods: 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 (AUC0 → 72 h) and half-life (t½). Creatinine, total bilirubin, and sample quality indices were retrieved from routine clinical laboratory analyses. Results: 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 AUC0 → 72 h of 112.85 ± 34.09 h·μmol/L and a t½ of 17.15 ± 2.40 h. MTX C(p) and AUC0 → 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 AUC0 → 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. Conclusions: 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
