Science & Data Analytics Division, Research & Development, AstraZeneca K.K. 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan.
Science & Data Analytics Division, Research & Development, AstraZeneca K.K. 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan.
J Pharm Sci. 2021 Jan;110(1):438-445. doi: 10.1016/j.xphs.2020.03.014. Epub 2020 Mar 30.
Glycopyrronium bromide, a synthetic anticholinergic agent used to treat patients with chronic obstructive pulmonary disease (COPD), is eliminated from the body by renal excretion and therefore systemic exposure is expected to be increased in patients with decreasing renal function. Despite enrollment of patients with decreasing renal function to evaluate the impact of renal impairment on the pharmacokinetics of glycopyrronium in clinical studies, no patients with severe renal impairment were included. A physiologically based pharmacokinetic (PBPK) model was developed in patients with COPD with normal renal function and used to predict systemic exposure of glycopyrronium in patients with severe renal impairment. The model accurately predicted plasma concentration-time profiles in patients with normal renal function, and mild and moderate renal impairment; the predicted and observed AUC and C in these populations were similar. Compared to patients with normal renal function, a 1.20-, 1.45-, and 1.59-fold increase AUC was predicted in patients with mild, moderate, and severe renal impairment, respectively, suggesting dose adjustment is not necessary in patients with renal impairment. In conclusion, PBPK models, verified with clinical study data from patients with normal renal function, can potentially be used to predict the pharmacokinetics and recommended dose adjustment for patients with renal impairment.
溴化吡丙醇铵，一种用于治疗慢性阻塞性肺疾病（COPD）患者的合成抗胆碱能药物，通过肾脏排泄从体内消除，因此预计在肾功能下降的患者中，全身暴露量会增加。尽管在临床研究中招募了肾功能下降的患者来评估肾功能损害对吡丙醇铵药代动力学的影响，但没有包括严重肾功能损害的患者。在肾功能正常的 COPD 患者中开发了基于生理学的药代动力学（PBPK）模型，并用于预测严重肾功能损害患者中吡丙醇铵的全身暴露量。该模型准确预测了肾功能正常、轻度和中度肾功能损害患者的血浆浓度-时间曲线；这些人群中预测和观察到的 AUC 和 C 相似。与肾功能正常的患者相比，预测轻度、中度和重度肾功能损害患者的 AUC 分别增加 1.20、1.45 和 1.59 倍，这表明肾功能损害患者不需要调整剂量。总之，经过肾功能正常患者的临床研究数据验证的 PBPK 模型，可用于预测肾功能损害患者的药代动力学和推荐的剂量调整。
