Translational Sciences Group, Sarepta Therapeutics, Inc., 215 First St., Cambridge, MA, 02142, USA.
Biology Group, Sarepta Therapeutics, Inc., Cambridge, MA, USA.
Pharm Res. 2021 Oct;38(10):1731-1745. doi: 10.1007/s11095-021-03118-5. Epub 2021 Oct 20.
Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have shown promise in treating Duchenne muscular dystrophy (DMD). We evaluated a semi-mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) model to capture the relationship between plasma and muscle tissue exposure/response in mdx mice treated by mouse surrogate PPMO.
A single or repeated (every 4 weeks for 20 weeks) intravenous PPMO dose was administered to mdx mice (n = 6/timepoint). A PK/PD model was built to characterize data via sequential modeling. A 2-compartment model was used to describe plasma PK. A simultaneous tissue PK/PD model was subsequently developed: 2-compartment model to describe muscle PK; linked to an indirect response model describing stimulation of synthesis of skipped transcript, which was in turn linked to stimulation of synthesis of dystrophin protein expression.
Model performance assessment via goodness-of-fit plots, visual predictive checks, and accurate parameter estimation indicated robust fits of plasma PK and muscle PK/PD data. The model estimated a PPMO tissue half-life of 5 days-a useful parameter in determining the longevity of PPMOs in tissue and their limited accumulation after multiple doses. Additionally, the model successfully described dystrophin expression after single dosing and associated protein accumulation after multiple dosing (increasing ~ twofold accumulation from the first to last dose).
This first PK/PD model of a PPMO in a DMD disease model will help characterize and predict the time course of PK/PD biomarkers in mdx mice. Furthermore, the model framework can be used to develop clinical PK/PD models and can be extended to other exon-skipping therapies and species.
肽偶联的磷酰胺二酯吗啉代寡聚物（PPMOs）在治疗杜氏肌营养不良症（DMD）方面显示出了潜力。我们评估了一个半机械论的药代动力学（PK）和药效动力学（PD）模型，以捕捉用小鼠替代 PPMO 治疗的 mdx 小鼠中血浆和肌肉组织暴露/反应之间的关系。
单次或重复（每 4 周一次，共 20 周）静脉内给予 mdx 小鼠 PPMO 剂量（n = 6/时间点）。通过顺序建模构建 PK/PD 模型来描述数据。使用 2 室模型描述血浆 PK。随后开发了一个同时的组织 PK/PD 模型：2 室模型来描述肌肉 PK；与描述跳过转录物合成刺激的间接反应模型相链接，该模型又与肌营养不良蛋白表达合成刺激相链接。
通过拟合优度图、可视化预测检查和准确的参数估计对模型性能进行评估，表明对血浆 PK 和肌肉 PK/PD 数据的拟合稳健。该模型估计了 PPMO 组织半衰期为 5 天-这是确定 PPMO 在组织中的寿命及其在多次剂量后有限积累的有用参数。此外，该模型成功描述了单次给药后的肌营养不良蛋白表达，并与多次给药后的蛋白积累相关（从第一剂到最后一剂的积累增加了约两倍）。
这是在 DMD 疾病模型中进行的第一个 PPMO 的 PK/PD 模型，将有助于描述和预测 mdx 小鼠中 PK/PD 生物标志物的时间过程。此外，该模型框架可用于开发临床 PK/PD 模型，并可扩展到其他外显子跳跃疗法和物种。
