Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate

Aim: There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC _MTX in the range between 1000 and 1100μmoll ^-1h. Methods: A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10000 patients and test the efficacy of a dosing algorithm based on 24h MTX plasma concentrations to target the prespecified AUC _MTX. These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four. Results: The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C ₂₄ < 0.5μmoll ^-1 up to -35% in patients with MTX C ₂₄ > 12μmoll ^-1. The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC _MTX target between 1000 and 1100μmoll ^-1h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure. Conclusions: A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC _MTX and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL).