Abstract

Spontaneous baroreflex sensitivity (sBRS) can be used to assess cardiac autonomic function. The aim of this double-blind, placebo-controlled, randomized, 3-period, crossover study was to evaluate a non-invasive methodology for monitoring sBRS as a biomarker tool in early drug development. The sBRS was determined using the ratio of the R-R interval from a 5-lead electrocardiogram (ECG) to the continuous systolic blood pressure (SBP) from a finger probe using a Finapres® NOVA device. The sBRS was measured at baseline and after two different intravenous (IV) saline and one 10 µg/kg IV atropine bolus injections in 12 healthy male subjects on 3 different study days. The sBRS changed little from baseline following saline administration (intrasubject percent coefficient of variation 14.5% [95% CI: 10.20-24.96]) and values were reproducible across the two saline administrations (Pearson’s, Interclass, and Concordance Correlation Coefficient all ~0.80; Bradley-Blackwood for simultaneous test on means and variances p > 0.93in the morning session and p > 0.39 in the afternoon session). Following atropine, peak reduction in sBRS was ~56%. The pattern of the reduction was consistent with the time course of measured atropine plasma pharmacokinetics. A non-invasive methodology for monitoring sBRS is reproducible following saline and sensitive to atropineinduced changes in cardiac autonomic function in young healthy male subjects. This approach may be a valuable tool to study potential cardiac autonomic impacts of novel investigational medicinal products in early clinical development studies.