Burmeister Getz Elise, Stein Richard R, Fink Martin, Kulmatycki Kenneth, Baltcheva Irina, Weis Wendy, Shah Bharti, Lawitz Eric, Schmouder Robert
Biomedical Research, Novartis, Emeryville, California, USA.
Novartis Pharma AG, Basel, Switzerland.
Clin Pharmacol Ther. 2025 May;117(5):1358-1368. doi: 10.1002/cpt.3559. Epub 2025 Jan 24.
Iptacopan, a first-in-class complement factor B inhibitor acting proximally in the alternative complement pathway, has been shown to be safe and effective for patients with complement-mediated diseases. Iptacopan selectively binds with high affinity to factor B, a soluble, plasma-based, hepatically produced protein. Factor B is abundant in the circulation but can be saturated at the iptacopan clinical dose of 200 mg twice daily. Iptacopan pharmacokinetics (PK) are influenced by target binding. This target-mediated drug disposition (TMDD) behavior makes PK data useful for understanding target occupancy and motivates modeling of drug-target binding to connect exposure with pharmacological effect. A phase I hepatic impairment (HI) PK study measuring both total and unbound iptacopan PK profiles provided an opportunity to characterize the effect of variation in target concentration (due to varying hepatic function) on iptacopan PK. HI caused no change in total iptacopan exposure but increased unbound iptacopan exposure 1.38- to 3.72-fold in participants with mild, moderate, or severe HI relative to demographically matched participants with normal hepatic function, with the largest increases in severe HI. A two-site competitive binding model was developed to elucidate the relationship between iptacopan PK and factor B occupancy to characterize exposure thresholds for maximal target engagement. The model was used to assess alternative dose regimens to provide insight into how to approach dose recommendations for patients with severe HI. This study provides an example of small-molecule TMDD, a behavior typically associated with targeted biologics; its importance is too often underappreciated in small-molecule drug development.
Iptacopan是一种一流的补体因子B抑制剂，在替代补体途径中作用于近端，已被证明对补体介导疾病的患者安全有效。Iptacopan以高亲和力选择性结合因子B，因子B是一种可溶性、基于血浆、由肝脏产生的蛋白质。因子B在循环中含量丰富，但在Iptacopan临床剂量每日两次、每次200毫克时可能会饱和。Iptacopan的药代动力学（PK）受靶点结合的影响。这种靶点介导的药物处置（TMDD）行为使PK数据有助于理解靶点占有率，并推动对药物-靶点结合进行建模，以将暴露与药理效应联系起来。一项测量总Iptacopan和游离Iptacopan PK曲线的I期肝损伤（HI）PK研究提供了一个机会，来表征靶点浓度变化（由于肝功能不同）对Iptacopan PK的影响。与肝功能正常、人口统计学匹配的参与者相比，轻度、中度或重度HI参与者中，HI并未导致总Iptacopan暴露量发生变化，但游离Iptacopan暴露量增加了1.38至3.72倍，重度HI参与者中增加幅度最大。开发了一个双位点竞争结合模型，以阐明Iptacopan PK与因子B占有率之间的关系，从而表征最大靶点结合的暴露阈值。该模型用于评估替代给药方案，以深入了解如何为重度HI患者制定给药建议。本研究提供了一个小分子TMDD的例子，这种行为通常与靶向生物制剂相关；在小分子药物开发中，其重要性常常未得到充分重视。
