Bristol Myers Squibb, Princeton, New Jersey, USA.
Certara Strategic Consulting, Princeton, New Jersey, USA.
J Clin Pharmacol. 2021 Jan;61(1):52-63. doi: 10.1002/jcph.1696. Epub 2020 Jul 21.
β-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent β-thalassemia often need lifelong regular RBC transfusions to maintain adequate hemoglobin levels. Frequent transfusions may lead to iron overload and organ damage. Thus, there is a large unmet need for alternative therapies. Luspatercept, a first-in-class erythroid maturation agent, is the first approved therapy in the United States for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. The population pharmacokinetics and exposure-response relationship of luspatercept were evaluated in 285 patients with β-thalassemia. Luspatercept displayed linear and time-invariant pharmacokinetics when administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept clearance, favoring weight-based dosing. Magnitude and frequency of hemoglobin increase, if not influenced by RBC transfusions, was positively correlated with luspatercept area under the serum concentration-time curve (AUC), 0.2-1.25 mg/kg, whereas a significant reduction in RBC units transfused was observed in frequently transfused patients. The probability of achieving ≥33% or ≥50% reduction in RBC transfusion burden was similar across the time-averaged AUC (0.6-1.25 mg/kg), with the 1 mg/kg starting dose sufficient for most early responders (71%-80%). Increasing luspatercept AUC (0.2-1.25 mg/kg) did not increase incidence or severity of treatment-emergent adverse events. These results provide a positive benefit-risk profile for the recommended luspatercept doses (1-1.25 mg/kg) in treating adult patients with β-thalassemia who require regular RBC transfusions.
β-地中海贫血是一种遗传性血液疾病，由血红蛋白生成缺陷引起，导致红细胞（RBC）或其前体过早死亡。依赖输血的β-地中海贫血患者通常需要终身定期接受 RBC 输血以维持足够的血红蛋白水平。频繁输血可能导致铁过载和器官损伤。因此，存在大量未满足的替代治疗需求。Luspatercept 是一种首创的红细胞成熟剂，是美国首个批准用于治疗需要定期接受 RBC 输血的成人β-地中海贫血患者贫血的治疗药物。在 285 名β-地中海贫血患者中评估了 luspatercept 的群体药代动力学和暴露-反应关系。皮下每 3 周给药一次时，luspatercept 表现出线性和时间不变的药代动力学。体重是 luspatercept 清除率的唯一有临床意义的协变量，支持基于体重的给药方案。如果不受 RBC 输血影响，血红蛋白增加的幅度和频率与血清浓度-时间曲线下面积（AUC）呈正相关，0.2-1.25 mg/kg，而频繁输血的患者观察到 RBC 单位输注显著减少。在时间平均 AUC（0.6-1.25 mg/kg）范围内，达到≥33%或≥50%减少 RBC 输血负担的概率相似，起始剂量 1 mg/kg 对大多数早期应答者（71%-80%）足够。增加 luspatercept AUC（0.2-1.25 mg/kg）不会增加治疗中出现的不良事件的发生率或严重程度。这些结果为推荐的 luspatercept 剂量（1-1.25 mg/kg）治疗需要定期接受 RBC 输血的成人β-地中海贫血患者提供了积极的获益风险特征。
