An Evaluation of Drug-Induced Blood Pressure Changes in a Standard Canine CV Safety Pharmacology Study: A HESI-sponsored Consortium

Elevated arterial blood pressure (BP) is highly correlated with adverse cardiovascular (CV) outcomes in patients. The effects of a drug on arterial pressure are routinely evaluated during preclinical safety assessment as outlined in the ICH S7A guidance document. A Health and Environmental Sciences Institute (HESI) Consortium initiated a multi-site study with the objective to assess the ability of the standard conscious telemetered CV beagle dog model to detect drug-induced changes in BP and evaluate translation to human data. Animals will be chronically instrumented with a BP catheter and ECG electrodes for telemetric collection of hemodynamic endpoints. 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) were selected based on known mechanisms of action as well as availability of clinical exposure data. Drugs will be evaluated in beagle dogs using a single (4 × 4) or double (8 × 4) Latin square design. Drugs will be administered orally at 3 doses selected to match clinical exposure data and a vehicle control. A full pharmacokinetic profile for each drug will be conducted at the doses selected at a single site (Abbvie). Blood samples at participating sites will be drawn to confirm drug exposures predicted from independent pharmacokinetic studies. The goal of these studies is to determine whether the assessment of BP, when measured across different laboratories using the same protocol, can consistently detect drug-induced changes in hemodynamics using drugs known to clinically increase and decrease BP.