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

被引:2
作者
Fukaya, Yutaka [1 ]
Kimura, Toshimi [2 ]
Hamada, Yukihiro [1 ]
Yoshimura, Kenichi [3 ]
Hiraga, Hiroaki [4 ]
Yuza, Yuki [5 ]
Ogawa, Atsushi [6 ]
Hara, Junichi [7 ]
Koh, Katsuyoshi [8 ]
Kikuta, Atsushi [9 ]
Koga, Yuhki [10 ]
Kawamoto, Hiroshi [11 ]
机构
[1] Tokyo Womens Med Univ Hosp, Dept Pharm, Tokyo, Japan
[2] Juntendo Univ Hosp, Dept Pharm, Tokyo, Japan
[3] Hiroshima Univ Hosp, Ctr Integrated Med Res, Hiroshima, Japan
[4] Natl Hosp Org Hokkaido Canc Ctr, Dept Musculoskeletal Oncol, Sapporo, Japan
[5] Tokyo Metropolitan Childrens Med Ctr, Dept Hematol & Oncol, Tokyo, Japan
[6] Niigata Canc Ctr Hosp, Dept Pediat, Niigata, Japan
[7] Osaka City Gen Hosp, Dept Pediat Hematol Oncol, Osaka, Japan
[8] Saitama Childrens Med Ctr, Dept Hematol Oncol, Saitama, Japan
[9] Fukushima Med Coll, Dept Pediat Oncol, Fukushima, Japan
[10] Kyushu Univ, Dept Perinatal & Pediat Med, Fukuoka, Japan
[11] Natl Canc Ctr, Dept Pediat Oncol, Tokyo, Japan
来源
FRONTIERS IN ONCOLOGY | 2023年 / 13卷
关键词
glucarpidase; methotrexate; adverse effects; safety; pharmacokinetics; pharmacodynamics; CANCER-PATIENTS; CARBOXYPEPTIDASE-G(2) RESCUE; RENAL DYSFUNCTION; ELIMINATION; ADULT;
D O I
10.3389/fonc.2023.1003633
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
IntroductionGlucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. MethodsIn 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 mu mol/L, was administered to the patient more than 46 h after the start of CPG2 administration. ResultsThe population mean PK parameters (95% CI) of MTX, obtained from the final model post hoc, were estimated as follows: CLrMTX = 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 alpha = 8.131 x 10(5) (4.864 x 10(5)-11.398 x 10(5)). The final model, including covariates, was CLrMTX (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 alpha (L/h): 6.545 x 10(5) (CV 79.8%). DiscussionThese 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 mu mol/L 48 h after the first CPG2 dosing.
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页数:11
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