Safety pharmacology core battery: Cardiovascular system

In vivo

Aim:

The aim of this type of study is, to examine the effects of the test item on cardiovascular parameters in telemetered, freely moving conscious animals.

Species:

In dogs or minipigs

Design:

• Latin square or sequential session design
• Parallel design in naïve animals for biologics
• Limit test or 3 dose groups with negative control
• In 2 sexes if sex differences are expected
• Optional with exposure control at Cmax

Outcome:

• The following parameters are recorded and evaluated:
  • Arterial blood pressure (systolic, diastolic and mean)
  • Heart rate
  • ECG parameters (including QT and corrected QT values)

In vitro

Aim:

This in vitro electrophysiology study is designed to gain information concerning the effect of a test item on action potential duration and/or cardiac ionic currents. The human ether-a-go-go related gene (hERG) encodes the inward rectifying voltage gated potassium channel in the heart (IKr). The most common mechanism of QT interval prolongation by pharmaceuticals is inhibition of this channel.

Reduced function of hERG channel lengthens ventricular action potentials, prolongs the QT interval in an electrocardiogram, and increases the risk for potentially fatal ventricular arrhythmias.

This inhibition potential of a test item should be determined early in the drug development.

Test system:

One of the hERG tests is an in vitro patch-clamp assay where mammalian cell lines stably expressing hERG channel gene are used.

Design and outcome:

The test item can be evaluated from 1 to 5 concentrations. The dose-response curve and IC50 value are generated after a limit test. Positive control is tested to ensure the sensitivity of the test system.