Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.
Yeamin Huh, Jessica Wojciechowski, Vivek S Purohit
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引用次数: 0
Abstract
Background and objectives: As drug development scientists strive to accelerate availability of therapies for patients, model-informed drug development (MIDD) plays an important role in contextualizing existing information and facilitating decision making. This paper describes an example of MIDD, where modeling and simulation informed decision making in the circumstance of a combined phase 2b and single pivotal study for ritlecitinib (JAK3/TEC family kinases inhibitor).
Methods: Longitudinal exposure-response (ER) modeling was conducted to describe ritlecitinib efficacy in alopecia areata patients. The Severity of Alopecia Tool (SALT) score (a continuous bounded outcome [CBO] score [0-100]) was used as the efficacy response. The average concentration during the time interval between two adjacent SALT scores was used as the exposure metric driving efficacy.
Results: The developed model well described the longitudinal SALT profile of ritlecitinib as well as the frequency of boundary data. The CBO model indicated tested doses in the phase 2b/3 clinical trial are in the ascending region of ER and contextualized a loading dose effect that impacted onset of efficacy without long-term benefit. It also identified disease severity as the only covariate impacting efficacy. The model-based simulation further informed impact of treatment interruption on the loss of efficacy in the absence of a dedicated treatment withdrawal study. Results indicated temporary treatment interruption ≤ 6 weeks is not expected to result in significant loss of efficacy.
Conclusion: The CBO modeling approach and simulation supported the single pivotal trial strategy and guided dose selection in the accelerated drug development program of ritlecitinib, which can be applied to many indications where efficacy is measured on a bounded scale.
背景和目标:随着药物开发科学家努力加快为患者提供治疗方法,模型信息药物开发(MIDD)在整合现有信息和促进决策制定方面发挥着重要作用。本文介绍了 MIDD 的一个实例,在对瑞替替尼(JAK3/TEC 家族激酶抑制剂)进行 2b 期和单一关键期联合研究时,建模和模拟为决策提供了依据:方法:采用纵向暴露-反应(ER)模型来描述利特西替尼对斑秃患者的疗效。脱发严重程度工具(SALT)评分(连续有界结果[CBO]评分[0-100])被用作疗效反应。相邻两次 SALT 评分之间的时间间隔内的平均浓度被用作衡量疗效的暴露指标:结果:所建立的模型很好地描述了利特西替尼的纵向 SALT 曲线以及边界数据的频率。CBO模型表明,2b/3期临床试验中的测试剂量处于ER的上升区域,并说明了影响起效但无长期获益的负荷剂量效应。该模型还确定疾病严重程度是影响疗效的唯一协变量。基于模型的模拟进一步说明了在缺乏专门的治疗中断研究的情况下,治疗中断对疗效丧失的影响。结果表明,暂时中断治疗≤6周预计不会导致显著的疗效损失:CBO建模方法和模拟支持了单一枢轴试验策略,并指导了利特西替尼加速药物开发计划中的剂量选择。
期刊介绍:
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.