Shah Kushal, Fischetti Briann, Cha Agnes, Taft David R
Samuel J. and Joan B. Williamson Institute for Pharmacometrics, Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn 11201, New York, United States.
Division of Pharmacy Practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn 11201, New York, United States.
Curr Drug Discov Technol. 2020;17(3):387-396. doi: 10.2174/1570163816666190214164916.
Lamivudine is a nucleoside reverse transcriptase inhibitor used to treat HIV and hepatitis B. It is primarily cleared by the kidney with renal secretion mediated by OCT2 and MATE.
To use PBPK modeling to assess the impact of renal impairment on lamivudine pharmacokinetics using the Simcyp® Simulator.
The model incorporated the Simcyp® Mechanistic Kidney Model option to predict renal disposition. The model was initially verified using the Simcyp® Healthy Volunteer population. Two discrete patient populations were then created for moderate (GFR 10-40 mL/min) and severe (GFR < 10 mL/min) renal failure (RF), and model simulations were compared to published data. The developed model was then utilized in a clinical study evaluating the clinical experience and plasma exposure of lamivudine when administered at higher than recommended doses to HIV-infected patients with varying degrees of renal impairment.
Predicted systemic exposure metrics (Cmax, AUC) compared favorably to published clinical data for each population, with the following fold errors (FE, ratio of predicted and observed data) for Cmax/AUC: Healthy Volunteers 1.04/1.04, Moderate RF 1.03/0.78, Severe RF 0.89/0.79. The model captured lamivudine plasma concentrations measured pre- and post-dose (0.5-1.5hr) in study participants (n = 34). Model simulations demonstrated comparable systemic profiles across patient cohorts, supporting the proposed dosage adjustment scheme.
This study illustrates how PBPK modeling can help verify dosing guidelines for patients with varying levels of renal impairment. This approach may also be useful for predicting potential changes in exposure during renal insufficiency for compounds undergoing clinical development.
拉米夫定是一种用于治疗艾滋病毒和乙型肝炎的核苷类逆转录酶抑制剂。它主要通过肾脏清除，由有机阳离子转运体2（OCT2）和多药及毒素排出蛋白（MATE）介导肾脏分泌。
使用生理药代动力学（PBPK）模型，通过Simcyp®模拟器评估肾功能损害对拉米夫定药代动力学的影响。
该模型纳入了Simcyp®机制性肾脏模型选项以预测肾脏处置。该模型最初使用Simcyp®健康志愿者群体进行验证。然后为中度（肾小球滤过率[GFR] 10 - 40 mL/分钟）和重度（GFR < 10 mL/分钟）肾衰竭（RF）创建了两个离散的患者群体，并将模型模拟结果与已发表的数据进行比较。然后将开发的模型用于一项临床研究，该研究评估了在高于推荐剂量下给不同程度肾功能损害的艾滋病毒感染患者服用拉米夫定时的临床经验和血浆暴露情况。
预测的全身暴露指标（Cmax、AUC）与各群体已发表的临床数据相比表现良好，Cmax/AUC的以下倍数误差（FE，预测值与观察值之比）分别为：健康志愿者1.04/1.04、中度RF 1.03/0.78、重度RF 分别为0.89/0.79。该模型捕捉到了研究参与者（n = 34）给药前和给药后（0.5 - 1.5小时）测量的拉米夫定血浆浓度。模型模拟显示不同患者队列的全身特征具有可比性，支持了建议的剂量调整方案。
本研究说明了PBPK建模如何有助于验证不同程度肾功能损害患者的给药指南。这种方法对于预测正在进行临床开发的化合物在肾功能不全期间暴露的潜在变化可能也有用。
