Department of Pharmacy, the First Affiliated Hospital of Fujian Medical University, Taijiang, Fuzhou, People's Republic of China.
Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
J Clin Pharmacol. 2020 Aug;60(8):999-1010. doi: 10.1002/jcph.1593. Epub 2020 Feb 24.
Pramipexole is the first-line medication recommended by the British National Institute for Health and Care Excellence. Pramipexole is predominantly eliminated by renal excretion. The aim was to develop a physiologically based pharmacokinetic (PBPK) model of pramipexole, providing a basis for its individualized administration. The role of glomerular filtration and organic cation transporter 2 (OCT2) in renal tubular secretion was considered. Plasma concentration-time profiles of pramipexole were predicted and validated, first in healthy populations and then in PD patients with varied renal function. Finally, the pharmacokinetics of PD patients with different degrees of renal impairment were predicted. The simulated pharmacokinetic parameters, including maximum plasma concentration (C ), area under the plasma concentration-time curve (AUC), time to maximum plasma concentration (t ), and steady-state trough plasma concentration values, obtained using the PBPK model were validated using fold error values, which were all smaller than 2. The successfully validated model supported that OCT2-mediated tubular secretion was affected proportionally to changes in glomerular filtration for various degrees of renal impairment. The predicted AUC values were increased 1.16-, 1.76-, 3.26-, and 9.48-fold in mild, moderate, and severe renal impairment and end-stage renal disease (ESRD) subjects, resepctively, compared with PD patients with normal renal function. It appears that PD patients with mild renal impairment are unlikely to require dose adjustment (0.125 mg 3 times a day). The pramipexole dose should be reduced to approximately 0.125 mg twice daily, 0.125 mg once daily, and 0.0375 mg once daily in PD patients with moderate renal impairment, severe renal impairment, and ESRD, respectively.
普拉克索是英国国家卫生与保健优化研究所推荐的一线药物。普拉克索主要通过肾脏排泄消除。本研究旨在建立普拉克索的生理基于模型的药代动力学（PBPK）模型，为其个体化给药提供依据。考虑了肾小球滤过和有机阳离子转运体 2（OCT2）在肾小管分泌中的作用。首先在健康人群中，然后在肾功能不同的 PD 患者中，预测和验证了普拉克索的血浆浓度-时间曲线。最后，预测了不同程度肾功能损害的 PD 患者的药代动力学。使用 PBPK 模型模拟的药代动力学参数，包括最大血浆浓度（C ）、血浆浓度-时间曲线下面积（AUC）、达峰时间（t ）和稳态谷值血浆浓度值，通过折叠误差值进行验证，所有值均小于 2。成功验证的模型表明，OCT2 介导的肾小管分泌与肾小球滤过成比例地受到各种程度肾功能损害的影响。与肾功能正常的 PD 患者相比，轻度、中度、重度和终末期肾病（ESRD）患者的预测 AUC 值分别增加了 1.16、1.76、3.26 和 9.48 倍。似乎轻度肾功能损害的 PD 患者不太可能需要调整剂量（每天 3 次，0.125 mg）。对于中度肾功能损害、重度肾功能损害和 ESRD 的 PD 患者，普拉克索的剂量应分别减少至约 0.125 mg 每日两次、0.125 mg 每日一次和 0.0375 mg 每日一次。
