Venuto Charles S, Yang Luoying, Javidnia Monica, Oakes David, James Surmeier D, Simuni Tanya
Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, New York, USA.
Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA.
Ann Clin Transl Neurol. 2021 Mar;8(3):603-612. doi: 10.1002/acn3.51300. Epub 2021 Jan 18.
Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression.
Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy.
Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, r : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (r : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02).
In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation.
ClinicalTrials.gov NCT02168842.
伊拉地平是一种二氢吡啶类钙通道抑制剂，在帕金森病（PD）动物模型中已显示出浓度依赖性神经保护作用，但在一项3期临床试验中未能显示出疗效。本研究的目的是对3期试验中研究参与者的伊拉地平血浆药代动力学进行建模；并研究药物暴露与PD进展的纵向临床结局指标之间的关联。
收集几乎所有随机接受每日两次5 mg速释伊拉地平治疗的研究参与者（170例中的166例）的血浆样本，用于群体药代动力学建模。伊拉地平暴露的估计值包括表观口服清除率和浓度-时间曲线下面积。测试伊拉地平暴露参数与疾病严重程度临床评估评分36个月变化的相关性，以及抗帕金森治疗开始的事件发生时间分析。
伊拉地平暴露与主要临床结局无关，即36个月内抗帕金森治疗调整后的统一帕金森病评定量表I-III部分评分的变化（斯皮尔曼等级相关系数，r：0.09，P = 0.23）。36个月时的累积左旋多巴等效剂量与伊拉地平血浆清除率弱相关（r：0.18，P = 0.035）。这种相关性存在性别差异，在男性中显著，但在女性中不显著。与安慰剂相比，伊拉地平暴露较高的患者在36个月内需要抗帕金森治疗的风险降低（风险比：0.87，95%CI：0.78-0.98，P = 0.02）。
在这项临床试验中，较高的伊拉地平血浆暴露并未影响PD严重程度的临床评估指标，但适度降低了累积左旋多巴等效剂量和开始抗帕金森治疗所需的时间。
ClinicalTrials.gov NCT02168842。
