Fukaya Yutaka, Kimura Toshimi, Hamada Yukihiro, Yoshimura Kenichi, Hiraga Hiroaki, Yuza Yuki, Ogawa Atsushi, Hara Junichi, Koh Katsuyoshi, Kikuta Atsushi, Koga Yuhki, Kawamoto Hiroshi
Department of Pharmacy, Tokyo Women's Medical University Hospital, Tokyo, Japan.
Department of Pharmacy, Juntendo University Hospital, Tokyo, Japan.
Front Oncol. 2023 Jan 30;13:1003633. doi: 10.3389/fonc.2023.1003633. eCollection 2023.
Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation.
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, = 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.
The population mean PK parameters (95% CI) of MTX, obtained from the final model , were estimated as follows: = 2.424 L/h (95% CI: 1.755-3.093), = 12.6 L (95% CI: 10.8-14.3), = 2.15 L (95% CI: 1.60-2.70), and = 8.131 x 10 (4.864 x 10-11.398 x 10). The final model, including covariates, was (L/h): 3.248 x /60 (CV 33.5%), (L): 0.386 x (CV 29.1%), (L):3.052 x /60 (CV 90.6%), and (L/h): 6.545 x 10 (CV 79.8%).
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.
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.
羧肽酶G2（CPG2）通过快速降解降低甲氨蝶呤（MTX）的致死毒性。
在本研究中，对健康志愿者进行了CPG2群体药代动力学（popPK）分析（1期研究），并对接受50 U/kg CPG2解救以促进MTX延迟排泄的患者进行了群体药代动力学-药效学（popPK-PD）分析（2期研究，n = 15）。在2期研究中，在首次确认MTX排泄延迟后的12小时内，静脉注射50 U/kg的首剂CPG2，持续5分钟。在CPG2给药开始后超过46小时，对血浆MTX浓度>1 μmol/L的患者给予第二剂CPG2。
从最终模型获得的MTX群体平均药代动力学参数（95%置信区间）估计如下：CL = 2.424 L/h（95%置信区间：1.755 - 3.093），V = 12.6 L（95%置信区间：10.8 - 14.3），Q = 2.15 L（95%置信区间：1.60 - 2.70），以及Ke = 8.131×10⁻⁴（4.864×10⁻¹¹.398×10⁻⁴）。包括协变量的最终模型为：CL（L/h）：3.248×Wt⁰.⁶⁰（变异系数33.5%），V（L）：0.386×Wt（变异系数29.1%），Q（L）：3.052×Wt⁰.⁶⁰（变异系数90.6%），以及Ke（L/h）：6.545×10⁻⁴（变异系数79.8%）。
这些结果表明，在贝叶斯估计48小时血浆MTX浓度预测时，CPG2给药前剂量和CPG2给药后24小时是最重要的采样点。这些CPG2-MTX群体药代动力学分析和血浆MTX浓度反弹的贝叶斯估计对于估计首次CPG2给药后48小时>1.0 μmol/L具有临床重要性。
