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Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy

INTRODUCTION: Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. METHODS: In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, n =...

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Autores principales: Fukaya, Yutaka, Kimura, Toshimi, Hamada, Yukihiro, Yoshimura, Kenichi, Hiraga, Hiroaki, Yuza, Yuki, Ogawa, Atsushi, Hara, Junichi, Koh, Katsuyoshi, Kikuta, Atsushi, Koga, Yuhki, Kawamoto, Hiroshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924065/
https://www.ncbi.nlm.nih.gov/pubmed/36793598
http://dx.doi.org/10.3389/fonc.2023.1003633
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author Fukaya, Yutaka
Kimura, Toshimi
Hamada, Yukihiro
Yoshimura, Kenichi
Hiraga, Hiroaki
Yuza, Yuki
Ogawa, Atsushi
Hara, Junichi
Koh, Katsuyoshi
Kikuta, Atsushi
Koga, Yuhki
Kawamoto, Hiroshi
author_facet Fukaya, Yutaka
Kimura, Toshimi
Hamada, Yukihiro
Yoshimura, Kenichi
Hiraga, Hiroaki
Yuza, Yuki
Ogawa, Atsushi
Hara, Junichi
Koh, Katsuyoshi
Kikuta, Atsushi
Koga, Yuhki
Kawamoto, Hiroshi
author_sort Fukaya, Yutaka
collection PubMed
description INTRODUCTION: Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. METHODS: In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, n = 15) who received 50 U/kg of CPG2 rescue for delayed MTX excretion were conducted. In the phase 2 study, the first CPG2 treatment at a dose of 50 U/kg was intravenously administered for 5 min within 12 h after the first confirmation of delayed MTX excretion. The second dose of CPG2, with a plasma MTX concentration >1 μmol/L, was administered to the patient more than 46 h after the start of CPG2 administration. RESULTS: The population mean PK parameters (95% CI) of MTX, obtained from the final model post hoc, were estimated as follows: CLr(MTX) = 2.424 L/h (95% CI: 1.755–3.093), Vc(MTX) = 12.6 L (95% CI: 10.8–14.3), Vp(MTX) = 2.15 L (95% CI: 1.60–2.70), and α = 8.131 x 10(5) (4.864 x 10(5)-11.398 x 10(5)). The final model, including covariates, was CLr(MTX) (L/h): 3.248 x Body Weight/Serum creatinine/60 (CV 33.5%), Vc(MTX) (L): 0.386 x Body Weight/body surface area (CV 29.1%), Vp(MTX) (L):3.052 x Body Weight/60 (CV 90.6%), and α (L/h): 6.545 x 10(5) (CV 79.8%). DISCUSSION: These results suggest that the pre-CPG2 dose and 24 h after CPG2 dosing were the most important sampling points in the Bayesian estimation of plasma MTX concentration prediction at 48 h. These CPG2-MTX popPK analysis and Bayesian estimation of rebound in plasma MTX concentrations are clinically important to estimate >1.0 μmol/L 48 h after the first CPG2 dosing. CLINICAL TRIAL REGISTRATION: https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2363, identifier JMA-IIA00078 and https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2782, identifier JMA-IIA00097.
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spelling pubmed-99240652023-02-14 Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy Fukaya, Yutaka Kimura, Toshimi Hamada, Yukihiro Yoshimura, Kenichi Hiraga, Hiroaki Yuza, Yuki Ogawa, Atsushi Hara, Junichi Koh, Katsuyoshi Kikuta, Atsushi Koga, Yuhki Kawamoto, Hiroshi Front Oncol Oncology INTRODUCTION: Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. METHODS: In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, n = 15) who received 50 U/kg of CPG2 rescue for delayed MTX excretion were conducted. In the phase 2 study, the first CPG2 treatment at a dose of 50 U/kg was intravenously administered for 5 min within 12 h after the first confirmation of delayed MTX excretion. The second dose of CPG2, with a plasma MTX concentration >1 μmol/L, was administered to the patient more than 46 h after the start of CPG2 administration. RESULTS: The population mean PK parameters (95% CI) of MTX, obtained from the final model post hoc, were estimated as follows: CLr(MTX) = 2.424 L/h (95% CI: 1.755–3.093), Vc(MTX) = 12.6 L (95% CI: 10.8–14.3), Vp(MTX) = 2.15 L (95% CI: 1.60–2.70), and α = 8.131 x 10(5) (4.864 x 10(5)-11.398 x 10(5)). The final model, including covariates, was CLr(MTX) (L/h): 3.248 x Body Weight/Serum creatinine/60 (CV 33.5%), Vc(MTX) (L): 0.386 x Body Weight/body surface area (CV 29.1%), Vp(MTX) (L):3.052 x Body Weight/60 (CV 90.6%), and α (L/h): 6.545 x 10(5) (CV 79.8%). DISCUSSION: These results suggest that the pre-CPG2 dose and 24 h after CPG2 dosing were the most important sampling points in the Bayesian estimation of plasma MTX concentration prediction at 48 h. These CPG2-MTX popPK analysis and Bayesian estimation of rebound in plasma MTX concentrations are clinically important to estimate >1.0 μmol/L 48 h after the first CPG2 dosing. CLINICAL TRIAL REGISTRATION: https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2363, identifier JMA-IIA00078 and https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2782, identifier JMA-IIA00097. Frontiers Media S.A. 2023-01-30 /pmc/articles/PMC9924065/ /pubmed/36793598 http://dx.doi.org/10.3389/fonc.2023.1003633 Text en Copyright © 2023 Fukaya, Kimura, Hamada, Yoshimura, Hiraga, Yuza, Ogawa, Hara, Koh, Kikuta, Koga and Kawamoto https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Fukaya, Yutaka
Kimura, Toshimi
Hamada, Yukihiro
Yoshimura, Kenichi
Hiraga, Hiroaki
Yuza, Yuki
Ogawa, Atsushi
Hara, Junichi
Koh, Katsuyoshi
Kikuta, Atsushi
Koga, Yuhki
Kawamoto, Hiroshi
Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy
title Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy
title_full Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy
title_fullStr Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy
title_full_unstemmed Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy
title_short Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy
title_sort development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924065/
https://www.ncbi.nlm.nih.gov/pubmed/36793598
http://dx.doi.org/10.3389/fonc.2023.1003633
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