Department of Pharmacy, Juntendo University Hospital, Tokyo, Japan.
Department of Pharmacy, Tokyo Women's Medical University Hospital, Tokyo, Japan;
Anticancer Res. 2023 May;43(5):1919-1924. doi: 10.21873/anticanres.16351.
Model-informed approaches are important in drug development, including for dose optimization and the collection of evidence in support of efficacy.
We developed a modified Michaelis-Menten pharmacokinetics/pharmacodynamics model and used it to conduct simulations of glucarpidase at doses between 10 and 80 U/kg rescue treatment after high-dose methotrexate therapy. We carried out a dose-finding modeling and simulation study before a phase II study of glucarpidase. Monte-Carlo simulations were conducted using the deSolve package of R software (version 4.1.2). The proportion of samples in which the plasma methotrexate concentration was less than 0.1 and 1.0 μmol/l at 70 and 120 h after methotrexate treatment was evaluated for each dosage of glucarpidase.
The proportion of samples in which the plasma methotrexate concentration was less than 0.1 μmol/l at 70 h after methotrexate treatment was 71.8% and 89.6% at 20 and 50 U/kg of glucarpidase, respectively. The proportion of samples in which the plasma methotrexate concentration was less than 0.1 μmol/l at 120 h after methotrexate treatment was 46.4% and 59.0% at 20 and 50 U/kg of glucarpidase, respectively.
We determined a recommended glucarpidase dose of 50 U/kg to be ethically acceptable. A rebound in the serum concentration of methotrexate may be observed in many patients after the administration of glucarpidase, and long-term monitoring (over 144 h) of the serum methotrexate concentration may be needed after the administration of glucarpidase. Its validity was confirmed in the phase II study and glucarpidase was approved for manufacturing in Japan.
模型指导方法在药物开发中很重要，包括剂量优化和支持疗效的证据收集。
我们开发了一个改良的米氏酶动力学/药效学模型，并用于模拟高剂量甲氨蝶呤治疗后 10 至 80 U/kg 剂量的葡醛酸酶解救治疗。我们在葡醛酸酶的 II 期研究之前进行了剂量探索建模和模拟研究。蒙特卡罗模拟使用 R 软件的 deSolve 包（版本 4.1.2）进行。评估了每个葡醛酸酶剂量下，在甲氨蝶呤治疗后 70 和 120 小时时，血浆中甲氨蝶呤浓度小于 0.1 和 1.0 μmol/l 的样本比例。
在甲氨蝶呤治疗后 70 小时时，血浆中甲氨蝶呤浓度小于 0.1 μmol/l 的样本比例分别为 71.8%和 89.6%，在 20 和 50 U/kg 的葡醛酸酶时。在甲氨蝶呤治疗后 120 小时时，血浆中甲氨蝶呤浓度小于 0.1 μmol/l 的样本比例分别为 46.4%和 59.0%，在 20 和 50 U/kg 的葡醛酸酶时。
我们确定 50 U/kg 的葡醛酸酶剂量在伦理上是可以接受的。在给予葡醛酸酶后，许多患者可能会观察到血清中甲氨蝶呤浓度的反弹，在给予葡醛酸酶后可能需要对血清中甲氨蝶呤浓度进行长达 144 小时的长期监测。在 II 期研究中证实了其有效性，葡醛酸酶在日本获得了批准生产。
