有效,但安全吗? 基于生理学的药理动力学 (PBPK) - 基于模拟的Molnupiravir的剂量研究,用于儿童亚群的风险评估
Sarang Mishra1, Katharina Rox1,2
1Department of Chemical Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
ACS pharmacology & translational science
|December 19, 2024
概括
口服抗病毒药物莫尔努皮拉维尔 (Molnupiravir) 对各种病毒具有潜力,但对儿童有毒性风险. 药物动力学建模表明,有效剂量可能超过安全限值,证实其适用于儿科的禁忌.
科学领域:
- 药理学 药理学是指药理学的学科.
- 毒理学 毒理学 毒理学
- 儿科医学 儿科医学
背景情况:
- 静脉注射雷姆迪西维尔是唯一批准用于弱势儿童的COVID-19治疗方法.
- 莫尔努皮拉维尔提供口服和广泛的抗病毒活性,但有潜在的骨和软骨毒性问题.
- 摩尔努皮拉维尔对埃博拉等高致命性病毒的有效性需要探索安全的儿科剂量.
研究的目的:
- 系统地调查molnupiravir在儿童群体中的骨和软骨毒性风险.
- 开发基于生理学的药理动力学 (PBPK) 模型,用于儿童用molnupiravir的剂量.
- 为了确定molnupiravir的有效剂量是否可以安全地给新生儿,婴儿和幼儿.
主要方法:
- 开发了用于molnupiravir剂量 (50-1200毫克) 的成人PBPK模型,其中包含CES1活性.
- 整合了CES1本位基因,以创建儿科PBPK剂量模型 (10-75 mg/kg).
- 计算了所需的molnupiravir剂量,以在儿科亚群中实现成人有效暴露 (AUC).
主要成果:
- 在儿童群体中达到成人有效AUC需要大约28 mg/kg每天两次 (BID).
- 这一剂量超过了在狗中观察到的安全剂量,并且接近于大鼠中人类相当的有毒剂量.
- 儿科PBPK模型表明,有效的molnupiravir剂量具有显著的毒性风险.
结论:
- 对于儿科患者群体的确定的molnupiravir有效剂量存在毒性风险.
- 这些发现支持molnupiravir对18岁以下人群的禁用.
- 对儿童群体安全的抗病毒选择进行进一步的研究是有必要的.
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