Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
Department of Neurosciences, University of Padova, Padua, Italy.
J Clin Pharmacol. 2024 Sep;64(9):1130-1140. doi: 10.1002/jcph.2446. Epub 2024 Apr 29.
Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A422, CYP3A41B), CYP3A5 (CYP3A53), and UGT1A1 (UGT1A160) utilizing population PK modeling. A one-compartment model with zero-order absorption (T, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population T was 3.14 h yielding an average zero-order absorption rate (k) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on T). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD.
人类遗传变异（多态性）在编码药物吸收、分布、代谢和消除（ADME）的蛋白质的基因中，可以对药物暴露和下游疗效和安全性结果产生强烈影响。Vamorolone 是一种用于治疗杜氏肌营养不良症（DMD）的分离甾体抗炎药，主要通过 CYP3A4 和 CYP3A5 氧化和 UDP-葡萄糖醛酸基转移酶（UGT）葡萄糖醛酸化。这项工作评估了 81 名类固醇初治的 DMD 男孩的 vamorolone 药代动力学（PK）和个体间变异性（IIV）的来源，这些男孩年龄在 4 至<7 岁，考虑了 CYP3A4（CYP3A422、CYP3A41B）、CYP3A5（CYP3A53）和 UGT1A1（UGT1A160）的遗传多态性，利用群体 PK 模型。一个一室模型，具有零级吸收（T，吸收持续时间）、线性清除率（CL/F）和体积（V/F），描述了接受广泛范围的 vamorolone 剂量（0.25-6 mg/kg/天）的 DMD 男孩的血浆 PK 数据。Vamorolone 的典型 CL/F 和 V/F 值分别为 35.8 L/h 和 119 L，具有适度的 IIV。人群 T 为 3.14 h，产生平均零级吸收速率（k）为 1.16 mg/kg/h，在相同的 vamorolone 剂量下，受试者的吸收动力学相似（即 T 无 IIV）。协变量分析表明，遗传协变量均对 DMD 男孩的 vamorolone PK 无显著影响。因此，在这些年轻的 DMD 男孩中，vamorolone 的 PK 非常一致。
