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 Howard, John T. Sandlund, Sima Jeha, Raul Ribeiro, Jeffrey Rubnitz, Ching Hon Pui, William E. Evans, Mary V. Relling

Research output: Contribution to journalArticle

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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/m2/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.

Original languageEnglish (US)
Pages (from-to)369-378
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume72
Issue number2
DOIs
StatePublished - Jan 1 2013

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Methotrexate
Toxicity
Plasmas
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Pauley, J. L., Panetta, J. C., Crews, K. R., Pei, D., Cheng, C., McCormick, J., ... Relling, M. V. (2013). Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. Cancer Chemotherapy and Pharmacology, 72(2), 369-378. https://doi.org/10.1007/s00280-013-2206-x

Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. / Pauley, Jennifer L.; Panetta, John C.; Crews, Kristine R.; Pei, Deqing; Cheng, Cheng; McCormick, John; Howard, Scott; Sandlund, John T.; Jeha, Sima; Ribeiro, Raul; Rubnitz, Jeffrey; Pui, Ching Hon; Evans, William E.; Relling, Mary V.

In: Cancer Chemotherapy and Pharmacology, Vol. 72, No. 2, 01.01.2013, p. 369-378.

Research output: Contribution to journalArticle

Pauley, JL, Panetta, JC, Crews, KR, Pei, D, Cheng, C, McCormick, J, Howard, S, Sandlund, JT, Jeha, S, Ribeiro, R, Rubnitz, J, Pui, CH, Evans, WE & Relling, MV 2013, 'Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments', Cancer Chemotherapy and Pharmacology, vol. 72, no. 2, pp. 369-378. https://doi.org/10.1007/s00280-013-2206-x
Pauley, Jennifer L. ; Panetta, John C. ; Crews, Kristine R. ; Pei, Deqing ; Cheng, Cheng ; McCormick, John ; Howard, Scott ; Sandlund, John T. ; Jeha, Sima ; Ribeiro, Raul ; Rubnitz, Jeffrey ; Pui, Ching Hon ; Evans, William E. ; Relling, Mary V. / Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 72, No. 2. pp. 369-378.
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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/m2/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.",
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AU - Panetta, John C.

AU - Crews, Kristine R.

AU - Pei, Deqing

AU - Cheng, Cheng

AU - McCormick, John

AU - Howard, Scott

AU - Sandlund, John T.

AU - Jeha, Sima

AU - Ribeiro, Raul

AU - Rubnitz, Jeffrey

AU - Pui, Ching Hon

AU - Evans, William E.

AU - Relling, Mary V.

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N2 - 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/m2/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.

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