Abstract：
OBJECTIVE: To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses.
METHODS: A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed.
RESULTS: Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5 mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6 mmol) by week 52.
CONCLUSIONS: The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6 years with relatively preserved kidney function.
METHODS: A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed.
RESULTS: Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5 mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6 mmol) by week 52.
CONCLUSIONS: The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6 years with relatively preserved kidney function.
摘要：
目的：为了表征奈多西兰在原发性高草酸尿症1型（PH1）患者中的药代动力学和药效学特征，确定有影响的协变量并确认治疗剂量。
方法：建立了群体药代动力学（PK）/药效学（PD）（POP-PKPD）模型，以表征奈多西兰的浓度-时间过程以及对24小时尿草酸盐（Uox）的相应作用。模拟剂量以实现临床上有意义的减少儿童Uox，进行了青少年和成人PH1。
结果：分析包括来自143名健康参与者和PH1/PH2患者的PK数据，和46例PH1患者的PD数据。NedosiranPK由具有双n传输吸收以及并行线性和非线性消除的两室模型描述。通过间接反应模型描述了奈多西兰暴露与Uox之间的关系。体重,估计的肾小球滤过率(eGFR)和疾病状态被确定为POP-PK模型的影响协变量.模拟结果支持在青少年和成人（≥12岁）中使用170mg（体重≥50kg）和136mg（体重<50kg）的奈多西兰钠的体重带给药方案，在PH1为3.5mg/kg的儿童（6-11岁）中，对于肾功能相对保留的PH1患者（eGFR≥30mL/min/1.73m2），未进行剂量调整。按照建议的给药方案，PKAUC0-τ的模拟中位数倍数变化，ss是可接受的(≤1.51倍变化),所有年龄组中~71%的PH1患者在第52周时达到接近正常的Uox(<0.6mmol).
结论：最终的POP-PKPD模型表征了观察到的奈多西兰PK和Uox数据。模拟支持在年龄≥6岁且肾功能相对保留的PH1患者中使用奈多西兰给药方案。
方法：建立了群体药代动力学（PK）/药效学（PD）（POP-PKPD）模型，以表征奈多西兰的浓度-时间过程以及对24小时尿草酸盐（Uox）的相应作用。模拟剂量以实现临床上有意义的减少儿童Uox，进行了青少年和成人PH1。
结果：分析包括来自143名健康参与者和PH1/PH2患者的PK数据，和46例PH1患者的PD数据。NedosiranPK由具有双n传输吸收以及并行线性和非线性消除的两室模型描述。通过间接反应模型描述了奈多西兰暴露与Uox之间的关系。体重,估计的肾小球滤过率(eGFR)和疾病状态被确定为POP-PK模型的影响协变量.模拟结果支持在青少年和成人（≥12岁）中使用170mg（体重≥50kg）和136mg（体重<50kg）的奈多西兰钠的体重带给药方案，在PH1为3.5mg/kg的儿童（6-11岁）中，对于肾功能相对保留的PH1患者（eGFR≥30mL/min/1.73m2），未进行剂量调整。按照建议的给药方案，PKAUC0-τ的模拟中位数倍数变化，ss是可接受的(≤1.51倍变化),所有年龄组中~71%的PH1患者在第52周时达到接近正常的Uox(<0.6mmol).
结论：最终的POP-PKPD模型表征了观察到的奈多西兰PK和Uox数据。模拟支持在年龄≥6岁且肾功能相对保留的PH1患者中使用奈多西兰给药方案。
