Reproducible safety pharmacology echocardiography studies in vehicle-treated canines and NHPs

Abstract

Echocardiography has emerged as a key component in cardiovascular diagnostics, offering a non-invasive, clinically relevant approach. Echocardiography enables the ability monitor disease progression, therapeutic responses, efficacy and safety of gene therapy interventions, as well as detecting cardiac toxicity. Typical measurements include the assessment of left ventricular (LV) systolic and diastolic function to evaluate overall cardiac performance, LV wall thickness/chamber size, evaluation of mitral and tricuspid regurgitation (MR/TR) to identify valvular defects, quantification of right ventricular performance (TAPSE and pulmonary velocities), left atrial annulus tissue doppler, as well as measurement of left atrial size/function to assess atrial performance. To determine the reproducibility and consistency of echocardiographic measurements, vehicle-treated animals were studied. Canines and non-human primates (NHPs) were sedated with butorphanol (0.2 mg/kg, IV) or ketamine (10 mg/kg, IM), respectively. In the canine study, echocardiographic measurements were collected in 4 animals at baseline and 6 h post vehicle (oral gavage). Of the 43 measured parameters, 40 were within 10 % of baseline. In the NHP study (n = 4), longitudinal vehicle data was collected at baseline, 6- and 12-weeks post intervention and demonstrated similar precision and reproducibility as all parameters were less than 15 % change from baseline at 6 weeks (32 out of 37 under 10 %). At 12 weeks, 35 of 37 were less than 15 % and 29 of 37 were under 10 %. In conclusion, incorporating high-quality and reproducible echocardiographic assessments into safety pharmacology studies offers a significant advantage by providing critical insights into cardiac function. However, the sonographer, ultrasound machine, and technique must be constant to detect a small difference in safety pharmacology studies.