Characterization of vasoactive agents in a canine safety pharmacology PKPD model: A HESI initiative

Abstract

Increases in arterial blood pressure (BP) contribute to adverse cardiovascular (CV) outcomes in patients; preclinical effects of a drug on BP are routinely evaluated during the safety pharmacology assessments as outlined in the ICH S7A guidance. A Health and Environmental Sciences Institute (HESI) Consortium initiated a multi-site study with the objective to assess the ability of the standard conscious telemetry instrumented CV dog model to detect drug-induced changes in BP and evaluate translation to human data. The goal of these studies is also to determine the reproducibility and consistency of BP assessment when measured across different laboratories using the same study protocol and recording methodology to detect drug-induced changes in hemodynamics using drugs known to clinically elevate and reduce BP. Animals were chronically instrumented with a BP catheter and ECG electrodes for telemetric collection of hemodynamic and ECG endpoints, respectively. Study endpoints include systolic, diastolic, and mean BP, heart rate, electrocardiogram (ECG), body temperature, and locomotor activity. Drugs evaluated include midodrine (alpha-1 agonist), nifedipine (calcium channel blocker), hydralazine (direct-acting smooth muscle relaxant), prazosin (alpha-1 blocker) and milrinone (phosphodiesterase-3 inhibitor). Drugs were selected based on known pharmacological mechanisms of action, primary cardiovascular effects as well as availability of clinical effect and exposure data. Drugs were evaluated in beagle dogs using a double (8 × 4) Latin square design and administered orally at 3 doses selected to match clinical exposure data with a vehicle control. A full pharmacokinetic profile for each drug was conducted in dogs at doses selected using automated blood sampling (ABS). Initial analysis shows that all 5 positive control drugs show consistent hemodynamic profiles (e.g., BP elevation or reduction) in the dog as seen in humans. These data sets with additional testing at multiple sites will be amenable to further statistical analysis, super-interval analysis and follow-up study endpoint evaluation such as pressure waveform analysis. The results from this chronically instrumented conscious dog model will provide essential information about accuracy and consistency in blood pressure measurement across multiple sites and translation of preclinical BP data to clinical outcomes.