Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments

Jennifer L Pauley, John C Panetta, Kristine R Crews, Deqing Pei, Cheng Cheng, John McCormick, Scott C Howard, John T Sandlund, Sima Jeha, Raul Ribeiro, Jeffrey Rubnitz, Ching-Hon Pui, William E Evans, Mary V Relling, Jennifer L Pauley, John C Panetta, Kristine R Crews, Deqing Pei, Cheng Cheng, John McCormick, Scott C Howard, John T Sandlund, Sima Jeha, Raul Ribeiro, Jeffrey Rubnitz, Ching-Hon Pui, William E Evans, Mary V Relling

Abstract

Purpose: It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments.

Methods: In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual's previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 μM (approximately 2.5 or 5 g/m(2)/day) for low- and standard-/high-risk patients, respectively.

Results: Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3-4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003).

Conclusions: Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.

Figures

Fig. 1
Fig. 1
Methotrexate clearance, MTX CL (ml/min/m2), by course and risk arm. The horizontal line in each box represents the median, the shaded boxes represent the quartiles, and the whiskers represent the range observed in patients for each course. The solid horizontal line across all courses represents the population clearance for all courses
Fig. 2
Fig. 2
Percentage of courses based on achieved MTX plasma steady-state concentrations (Cpss) (individualized therapy) compared to the percentage predicted based on conventional dosing (simulated for fixed doses). The groups are defined as follows: Dark Blue Cpss greater than 50 % below target Cpss, Light Blue Cpss between 20 and 50 % below target, Green Cpss within ±20 % of the target, Yellow Cpss between 20 and 50 % above target, Red Cpss greater than 50 % above target. *Significance (p < 0.001) in the difference in the proportion of courses between individualized therapy relative to simulated fixed dose therapy (otherwise p > 0.1). a Low-risk arm: target concentration: 33 μM. b Standard-/high-risk arm: target concentration: 65 μM

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