Certara, Inc., Menlo Park, California, USA.
Travere Therapeutics, Inc., San Diego, California, USA.
CPT Pharmacometrics Syst Pharmacol. 2023 Aug;12(8):1080-1092. doi: 10.1002/psp4.12996. Epub 2023 Jun 1.
Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.
斯巴森坦是一种单分子双重内皮素血管紧张素受体拮抗剂（DEARA），目前正在研究用于局灶节段性肾小球硬化症（FSGS）和 IgA 肾病（IgAN）的治疗。进行了群体药代动力学（PK）分析，以描述斯巴森坦的 PK，并评估 FSGS 疾病特征和伴随药物作为协变量对斯巴森坦 PK 的影响。从 I 期到 III 期的 9 项研究中，共招募了 236 名健康志愿者、16 名肝损伤患者和 194 名原发性和遗传性 FSGS 患者，采集了血样。使用经验证的液相色谱-串联质谱法（LC-MS/MS）测定斯巴森坦的血浆浓度，定量下限为 2ng/mL。采用一阶条件估计与 η-ϵ 相互作用（FOCE-1）法在 NONMEM 中进行模型构建。使用单变量正向添加和逐步向后消除分析测试了总共 20 个协变量，显著性水平分别为 p<0.01 和 p<0.001。采用具有一级吸收和吸收滞后时间的两室模型以及比例加附加残差（2ng/mL）来描述斯巴森坦的 PK。在稳态时，由于 CYP3A 自动诱导，清除率增加了 32%。保留在最终模型中的协变量包括制剂、CYP3A4 抑制剂共同给药、性别、种族、肌酐清除率和血清碱性磷酸酶。中度和强 CYP3A4 抑制剂联合用药使 AUC 增加了 31.4%和 191.3%。该斯巴森坦群体 PK 模型表明，同时服用中度和强 CYP3A4 抑制剂的患者可能需要调整剂量，但分析的其他协变量可能不需要调整剂量。
