Using SPAR to analyze arterial blood pressure waves, following fostamatinib and entospletinib administration in radiotelemetry in rats, to aid in cardiovascular safety testing

Abstract

Cardiovascular safety liabilities represent a leading cause of drug attrition, and improved preclinical measurements are essential to predict drug-related toxicities (Cook et al., 2014; Weaver & Valentin, 2019). Presently, radiotelemetry approaches recording blood pressure are routinely used in preclinical in vivo assessments. Typically, single points of these waveforms (e.g. mean arterial pressure (MAP)) are used for analysis. Although MAP provides important insights, this approach overlooks potential information hidden in changes in waveform morphology and variability. The Symmetric Projection Attractor Reconstruction (SPAR) is a novel mathematical method that enables detailed wave analysis, transforming lengthy waveform recordings into contained visual 2D representations (attractors) (Nandi & Aston, 2020). By subsequent analysis of key features of the attractor (e.g. rQ25, indicating the opening of the attractor), subtle changes in the cardiovascular system can be detected. The objective of the present study was to explore in-depth characterization of arterial blood pressure waves after drug administration. Fostamatinib, a Syk-inhibitor causing hypertension due to off-target VEGFR2-inhibition, and entospletinib, designed for better selectivity and less adverse effects, are presented as an example of how in-depth wave analysis could improve cardiovascular safety testing. Male Wistar rats were instrumented with Stellar telemetry implants. Arterial blood pressure was recorded over two consecutive days, for at least 1 h before and up to 23 h after daily administration of fostamatinib (20 mg/kg, p.o.) or entospletinib (6 mg/kg, p.o), alongside a vehicle control (10 mL/kg, p.o.). Fostamatinib increased MAP significantly on day 2 (p < 0.05, Two-way ANOVA); there was no significant effect on MAP on day 1. Entospletinib did not affect MAP significantly. Fostamatinib caused changes in waveform morphology, that were quantified using attractor parameters. Attractor opening increased significantly from day 1 of fostamatinib administration (e.g. rQ25 p < 0.05, Two-way ANOVA). These fostamatinib-induced attractor changes were opposite to the ones observed with vasodilators, associated with a decrease in attractor opening, therefore indicating that fostamatinib caused a vasoconstriction. This is consistent with literature, describing a fostamatinib-induced vasoconstriction due to VEGFR2-inhibition (Skinner et al. 2014). Moreover, entospletinib had similar but smaller effects on attractor opening (delta rQ25 p < 0.0005 on day 1, Two-way ANOVA). Given that SPAR could detect fostamatinib-induced cardiovascular effects earlier than MAP, and SPAR could detect entospletinib-induced changes in a more sensitive way than MAP, these data suggest that more extensive blood pressure waveform analysis using SPAR in telemetered rats may provide nuanced information that could aid in informed decision making and earlier detection of cardiovascular safety liabilities. This work was funded by the European Union's H2020 Research & Innovation Program (GA 858070).