Patel Munjal, Xu Huijuan, Barriere Olivier, Diderichsen Paul, Patwari Parth, Zhu Andy Z X, Marier Jean François, Peyret Thomas, Wang Linda T, Mellgård Björn, Wang Wenping, Bhattacharya Indranil
Takeda Development Center Americas, Inc., Cambridge, Massachusetts, USA.
Certara USA Inc., Princeton, New Jersey, USA.
Clin Pharmacol Ther. 2025 Oct;118(4):813-822. doi: 10.1002/cpt.3720. Epub 2025 Jun 5.
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, potentially life-threatening condition caused by a deficiency of the blood enzyme ADAMTS13. Until now, ADAMTS13 replacement has been achieved with infusions of plasma or plasma-based therapies (PBT). However, the quantitative relationship between ADAMTS13 plasma activity and clinical manifestations is poorly understood. We therefore conducted integrated population pharmacokinetics (PopPK) analysis and exposure-response modeling based on three clinical trials of recombinant ADAMTS13 (rADAMTS13, Takeda Pharmaceuticals U.S.A., Inc.) in patients with cTTP. These aim to assess the clinical benefit of rADAMTS13, which at the proposed dose of 40 IU/kg provides ADAMTS13 peak levels of approximately 100% of normal levels. The PK model indicated that, besides body weight-based dosing, no further dose adjustment was required based on age or race. The only extrinsic covariates with a significant impact on ADAMTS13 plasma activity levels were dosing interval and treatment type (rADAMTS13 vs. PBT). The correlation between ADAMTS13 plasma activity levels and cTTP manifestations was investigated with three different exposure-response models. Increasing exposure to ADAMTS13, as measured by average activity over a one-to-two-week period, predicted the probability of disease manifestations, primarily assessed as thrombocytopenia. Model simulations predicted that >90% of patients treated with 40 IU/kg rADAMTS13 achieve an average ADAMTS13 plasma activity >13% of normal, which was shown to be highly protective against thrombocytopenia (>70% lower hazard). Similar results were observed for protection against elevation of lactate dehydrogenase, a marker of microangiopathic hemolytic anemia. Overall, these results support the use of rADAMTS13 treatment for patients with cTTP.
先天性血栓性血小板减少性紫癜（cTTP）是一种极为罕见的、可能危及生命的疾病，由血液中酶ADAMTS13缺乏引起。到目前为止，已通过输注血浆或基于血浆的疗法（PBT）来实现ADAMTS13的替代。然而，ADAMTS13血浆活性与临床表现之间的定量关系尚不清楚。因此，我们基于三项重组ADAMTS13（rADAMTS13，美国武田制药公司）治疗cTTP患者的临床试验，进行了综合群体药代动力学（PopPK）分析和暴露-反应建模。这些试验旨在评估rADAMTS13的临床益处，按提议剂量40 IU/kg给药时，rADAMTS13的峰值水平约为正常水平的100%。药代动力学模型表明，除了基于体重给药外，无需根据年龄或种族进一步调整剂量。对ADAMTS13血浆活性水平有显著影响的唯一外部协变量是给药间隔和治疗类型（rADAMTS13与PBT）。我们用三种不同的暴露-反应模型研究了ADAMTS13血浆活性水平与cTTP表现之间的相关性。通过一到两周期间的平均活性来衡量，ADAMTS13暴露增加可预测疾病表现的概率，主要评估指标为血小板减少症。模型模拟预测，接受40 IU/kg rADAMTS13治疗的患者中，>90%的患者ADAMTS13血浆平均活性>正常水平的13%，这已显示出对血小板减少症具有高度保护作用（风险降低>70%）。在预防作为微血管病性溶血性贫血标志物的乳酸脱氢酶升高方面也观察到了类似结果。总体而言，这些结果支持将rADAMTS13用于治疗cTTP患者。
