Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
Integrated Drug Development, Certara, Menlo Park, California, USA.
CPT Pharmacometrics Syst Pharmacol. 2022 Jun;11(6):687-697. doi: 10.1002/psp4.12731. Epub 2022 Apr 21.
Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.
奥贝胆酸（Oxbryta，voxelotor）是一种镰状血红蛋白（Hb）聚合的小分子抑制剂，适用于年龄≥ 12 岁的镰状细胞病（SCD）患者，剂量为 1500mg 每日一次（qd）。Voxelotor 优先与 Hb 结合，voxelotor 向红细胞的分配是 Hb 占有率的有效预测指标。这些分析的目的是建立成人和青少年血浆和全血中 voxelotor 的群体药代动力学（PopPK）模型，以支持最佳靶标结合的剂量选择，并确定对血浆和全血中 voxelotor 药代动力学（PK）有显著影响的协变量。一个具有两个隔室、一级吸收和消除以及作用部位效应隔室的整合血浆和全血 PopPK 模型，能够充分描述接受长达 72 周治疗的患者的 voxelotor 血浆和全血浓度-时间曲线。对 voxelotor PK 有显著影响的协变量包括表观中央隔室容积的基础血容量和时变血细胞比容以及全血分配的剂量，表明 voxelotor 效应的临床标志物可以反过来影响其 PK。此外，该模型证实 voxelotor 在血浆和全血中的 PK 与剂量和时间呈线性关系，并且在成人和青少年中是可比的。在这项分析中，未发现需要调整剂量的 voxelotor PK 有临床意义的协变量影响。总的来说，PopPK 分析对 voxelotor 的标签有重要贡献，并支持将 1500mg qd 作为 SCD 成人和青少年的治疗剂量。
