Maringwa John, Kågedal Matts, Hamrén Ulrika Wählby, Martin Paul, Cox Eugène, Hamrén Bengt
Quantitative Solutions BV, Breda, The Netherlands.
AstraZeneca Quantitative Clinical Pharmacology, Södertälje/Mölndal, Sweden.
J Clin Pharmacol. 2015 Mar;55(3):328-35. doi: 10.1002/jcph.406. Epub 2014 Nov 20.
R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.
R788（福他替尼）是一种口服前体药物，可迅速转化为相对选择性的脾酪氨酸激酶（SYK）抑制剂R406，目前正在评估其用于治疗类风湿性关节炎（RA）的效果。该分析旨在利用类风湿性关节炎患者两项II期研究（TASKi1和TASKi2）的汇总ACR20数据建立药效学模型以评估疗效，将福他替尼的效果描述为福他替尼暴露量（剂量、R406血浆浓度）及其他解释变量的函数。福他替尼的暴露-反应关系被纳入一个连续时间马尔可夫模型，该模型描述了每次访视时ACR20无反应者、反应者和退出者这三种可能状态之间转换概率的时间进程。向ACR20反应状态转换的概率与平均R406血浆浓度呈线性关系（在速率常数水平），且这种药物效应起效迅速。此外，福他替尼剂量增加会导致退出率上升以及随后疗效丧失。该分析增进了对暴露-反应关系的理解，并为福他替尼100mg每日两次这一合适的给药方案用于进一步临床评估提供了支持。
