BACKGROUND AND OBJECTIVES The elderly population receives the majority of prescription drugs but are usually excluded from Phase 1 clinical trials. Alternative approaches to estimate increases in toxicity risk or decreases in efficacy are therefore needed. This study predicted the pharmacokinetics (PK) of three renally excreted antiretroviral drugs in the elderly population and compared them with known exposures in renal impairment, to evaluate the need for dosing adjustments. METHODS The performance of the physiologically based pharmacokinetic (PBPK) models for tenofovir, lamivudine and emtricitabine were verified using clinical data in young and older subjects. Models were then used to predict PK profiles in a virtual population aged 20 to 49 years (young) and a geriatric population aged 65 to 74 years (elderly). Predicted exposure in the elderly was then compared with exposure reported for different degrees of renal impairment, where doses have been defined. RESULTS An increase in exposure (AUC) with advancing age was predicted for all drugs. The mean ratio of the increase in exposure were 1.40 for emtricitabine, 1.42 for lamivudine and 1.48 for tenofovir. The majority of virtual patients had exposures that did not require dosage adjustments. About 22% of patients on tenofovir showed exposures similar to that in moderate renal impairment, where dosage reduction may be required. CONCLUSION Comparison of the exposure in the elderly with exposure observed in patients with different levels of renal impairment, indicated that a dosage adjustment may not be required in elderly patients on lamivudine, emtricitabine and the majority of the patients on tenofovir. Clinical trials to verify these predictions are essential.

中文翻译：

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老年患者经肾脏排泄的抗逆转录病毒药物的标准剂量是否适当：一项PBPK研究比较了老年人群与肾功能不全者的暴露水平。

背景和目标老年人接受大多数处方药，但通常不包括在1期临床试验中。因此需要估计毒性风险增加或功效降低的替代方法。这项研究预测了老年人中三种经肾脏排泄的抗逆转录病毒药物的药代动力学（PK），并将它们与已知的肾脏损害暴露进行比较，以评估剂量调整的必要性。方法使用青年和老年人受试者的临床数据验证替诺福韦，拉米夫定和恩曲他滨的基于生理的药代动力学（PBPK）模型的性能。然后，使用模型来预测20至49岁的虚拟人口（年轻人）和65至74岁的老年人口（老年人）的PK分布。然后将老年人的预期暴露与已报告的不同程度肾功能损害的暴露进行比较，并确定了剂量。结果预测所有药物的暴露量（AUC）随着年龄的增长而增加。恩曲他滨的暴露量增加的平均比率为1.40，拉米夫定为1.42，替诺福韦为1.48。大多数虚拟患者的暴露量无需调整剂量。替诺福韦治疗的患者中约22％的暴露水平与中度肾功能不全患者相似，可能需要减少剂量。结论比较老年人的暴露量与不同程度的肾功能不全患者的暴露量表明，拉米夫定的老年患者可能不需要调整剂量，恩曲他滨和大多数患者使用替诺福韦。验证这些预测的临床试验至关重要。