Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials.

Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.

Comparison of electrocardiogram and blood pressure recording methods in non-rodent toxicology studies: A retrospective analysis.

Our study retrospectively examines 51 non-rodent general toxicology studies conducted over the past 8 years to ascertain the influence of recording methodologies on baseline cardiovascular (CV) parameters and statistical sensitivity. Specifically, our work aims to evaluate the frequency of cardiovascular parameter recording categorized by therapeutic modality and study type, to assess the variability in these parameters based on measurement techniques, and to determine the sample sizes needed for detecting relevant changes in heart rate (HR), blood pressure (BP), and QTc interval in non-human primate (NHP) studies. Results indicate that electrocardiogram (ECG) measurements in dogs and NHP were recorded in 63% of studies, combined with BP recording in 18% of studies, while BP was never recorded alone.

The state of the art in secondary pharmacology and its impact on the safety of new medicines.

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development.