Eli Lilly and Company, Erl Wood Manor, Windlesham, UK.
Université de Paris Descartes, Paris, France.
Basic Clin Pharmacol Toxicol. 2018 Feb;122(2):245-252. doi: 10.1111/bcpt.12900. Epub 2017 Sep 27.
Event-related potentials (ERPs) are commonly used in Neuroscience research, particularly the P3 waveform because it is associated with cognitive brain functions and is easily elicited by auditory or sensory inputs. ERPs are affected by drugs such as lorazepam, which increase the latency and decrease the amplitude of the P3 wave. In this study, auditory-evoked ERPs were generated in 13 older healthy volunteers using an oddball tone paradigm, after administration of single 0.5 and 2 mg doses of lorazepam. Population pharmacokinetics (PK)/pharmacodynamics (PD) models were developed using nonlinear mixed-effects methods in order to assess the effect of lorazepam on the latency and amplitude of the P3 waveforms. The PK/PD models showed that doses of 0.3 mg of lorazepam achieved approximately half of the maximum effect on the latency of the P3 waveform. For P3 amplitude, half the maximum effect was achieved with a dose of 1.2 mg of lorazepam. The PK/PD models also predicted an efficacious dose range of lorazepam, which was close to the recommended therapeutic range. The use of longitudinal P3 latency data allowed better predictions of the lorazepam efficacious dose range than P3 amplitude or aggregate exposure-response data, suggesting that latency could be a more sensitive parameter for drugs with similar mechanisms of action as lorazepam and that time course rather than single time-point ERP data should be collected. Overall, the results suggest that P3 ERP waveforms could be used as potential non-specific biomarkers for functional target engagement for drugs with brain activity, and PK/PD models can aid trial design and choice of doses for development of new drugs with ERP activity.
事件相关电位（ERPs）在神经科学研究中被广泛应用，特别是 P3 波，因为它与认知脑功能有关，并且容易被听觉或感觉输入引发。药物如劳拉西泮会影响 ERPs，增加 P3 波的潜伏期并降低其幅度。在这项研究中，给 13 名老年健康志愿者单次服用 0.5mg 和 2mg 劳拉西泮后，使用偶发性音调范式生成听觉诱发的 ERPs。采用非线性混合效应方法建立群体药代动力学（PK）/药效动力学（PD）模型，以评估劳拉西泮对 P3 波潜伏期和幅度的影响。PK/PD 模型表明，0.3mg 劳拉西泮剂量约达到对 P3 波潜伏期最大效应的一半。对于 P3 幅度，达到最大效应的一半需要 1.2mg 劳拉西泮剂量。PK/PD 模型还预测了劳拉西泮的有效剂量范围，接近推荐的治疗范围。使用纵向 P3 潜伏期数据可以更好地预测劳拉西泮的有效剂量范围，而不是 P3 幅度或总暴露-反应数据，这表明潜伏期可能是与劳拉西泮具有相似作用机制的药物的更敏感参数，并且应该收集时间过程而不是单个时间点 ERP 数据。总的来说，这些结果表明，P3 ERP 波可以作为具有脑活性的药物功能靶标结合的潜在非特异性生物标志物，PK/PD 模型可以辅助试验设计和新药物剂量的选择，这些药物具有 ERP 活性。
