尼多西兰人群的药理动力学和药理动力学建模和模拟,以指导1型原发性高氧尿症患者的临床发展和剂量选择
Steven Zhang1, Aniruddha Amrite2, Beesan Tan3
1Dicerna Pharmaceuticals, Inc. a Novo Nordisk company, Lexington, Massachusetts, USA.
尼多西兰有效地降低了1型原发性高氧化尿 (PH1) 患者的尿氧酸. 对儿童,青少年和成年人来说,基于体重的剂量方案得到证实,确保治疗疗效.
科学领域:
- 药理学 药理学是指药理学的学科.
- 腎臟病學 (nephrology) 是一種醫學專業.
- 遗传学 是一个遗传学.
背景情况:
- 初级高氧化尿1型 (PH1) 是一种罕见的遗传性疾病.
- 尿氧酸 (Uox) 的升高会导致脏损伤和衰竭.
研究的目的:
- 在PH1患者中描述内多西兰的药理动力学 (PK) 和药理动力学 (PD) 概况.
- 确定影响内多西兰疗效的因素,并确认最佳治疗剂量.
主要方法:
- 使用PK和PD数据开发了一个人群PK/PD (POP-PKPD) 模型.
- 进行了模拟,以确定不同年龄组和体重组的剂量方案.
- 分析了体重和功能等共变量.
主要成果:
- 尼多西兰PK被描述为具有双吸收和混合线性/非线性消除的两模型.
- 体重,eGFR和疾病状况是显著的共变量.
- 青少年和成年人 (≥12岁) 支持按体重分组的剂量方案,儿童 (6-11岁) 则支持按体重分组的剂量方案.
- 大约71%的PH1患者在52周内达到接近正常的Uox水平.
结论:
- POP-PKPD模型准确地描述了内多西兰在PH1患者中的行为.
- 模拟支持为PH1年龄≥6岁,功能保留的PH1患者提出的尼多西兰剂量方案.
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