Validation of the normal, freely moving Göttingen minipig for pharmacological safety testing.
BACKGROUND
The objective of this study was to use a newly established cardiovascular model using freely moving minipigs to document the hemodynamic and electrocardiographic effects of known pharmacological agents. The data generated are to serve as the basis of pharmacological drug safety evaluations using this new model.


METHODS
6 Göttingen minipigs were equipped with a radiotelemetry system (ITS). Following a recovery period, aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body temperature were continuously recorded throughout an 8 h monitoring period following oral administration of one of the test agents or vehicle. Notocord HEM 4.2 software was used for data acquisition. One known hERG blocker (moxifloxacin (30, 100 or 300 mg/kg)) and one non-selective beta-adrenoreceptor antagonist (propranolol (3, 10 or 20 mg/kg)) were tested in the model using a cross-over study design in 6 pigs.


RESULTS
We obtained high signal quality and found stable hemodynamic parameters with low intrinsic heart rates in the Göttingen minipig under resting, pre-treatment conditions. After oral dosing of moxifloxacin, a substantial, dose-dependent increase in the QT-interval duration could be shown, as anticipated for this agent. After propranolol administration, a decrease in HR and left ventricular dP/dt was detected as expected for a beta-adrenoceptor blocking agent.


CONCLUSIONS
The present data demonstrate that using this model in conscious, chronically instrumented Göttingen minipigs, a cross-over study with six animals was sensitive enough to detect a dose-dependent QT prolongation when moxifloxacin was administered in oral doses leading to clinically relevant plasma drug concentrations. Additionally, we could demonstrate the expected propranolol-induced effects on heart rate and myocardial contractility, despite the low intrinsic resting heart rates in these minipigs. These data support the use of the Göttingen minipig as a sensitive cardiovascular and electrocardiographic model for the testing of new pharmaceutical agents.
Department of Drug Discovery Support, General Pharmacology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Germany. Michael.markert@bc.boehringer-ingelheim.com
Michael
M
Markert
Miriam
M
Stubhan
Karin
K
Mayer
Thomas
T
Trautmann
Anja
A
Klumpp
Annette
A
Schuler-Metz
Kurt
K
Schumacher
Brian
B
Guth
D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology; D001372:Aza Compounds / Q000009:adverse effects / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D000077266:Moxifloxacin; D011433:Propranolol / Q000009:adverse effects / Q000494:pharmacology; D011804:Quinolines / Q000009:adverse effects / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature; D013686:Telemetry / Q000295:instrumentation* / Q000379:methods*
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001372:Aza Compounds; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D011804:Quinolines; D011433:Propranolol; D000077266:Moxifloxacin