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Test article concentrations in the hERG assay: losses through the perfusion, solubility and stability.

Abstract：

INTRODUCTION:Drug-induced prolongation of the electrocardiographic QT interval (long QT syndrome) has been associated with increased risk of a serious ventricular arrhythmia, torsade de pointes. Inhibition of hERG, a cardiac potassium channel that controls action potential repolarization, is the most common cause of QT prolongation by non-cardiac drugs. The ICH S7B describes preclinical safety testing required for new drugs, including the determination of the hERG IC(50). Actual and target concentrations may differ due to solubility, stability, or loss of compound. Significant differences will invalidate quantitative concentration-response curves which may be critical to interpretation of drug safety. To examine the frequency and significance of these differences, we conducted an analysis of studies where both the electrophysiology and the dose solution analysis were conducted in-house. We have investigated the actual concentrations of test article in vehicle solution as compared to the target concentrations in an attempt to determine the reasons behind differences between the two values. METHODS:Studies that involved both electrophysiology and dose solution analysis performed at ChanTest Corporation were evaluated. The effects of stability, solubility and loss through the perfusion apparatus on actual dosing concentrations were investigated. RESULTS:There was a large range in the loss of the test article attributed to the perfusion apparatus (range from 0 to 74% loss). For 12 of the 22 studies evaluated, the IC(50) was>2-fold more potent when using actual values as determined by HPLC versus the target concentrations. Twenty-two percent of the test articles were not stable 24 h after room temperature storage; 16% after 24 h frozen conditions. DISCUSSION:The best practices when considering dose solution concentration verification of test article solutions are to: determine the solubility of the compound in a physiological buffer, analyze samples collected from the perfusion chamber, and analyze samples the same day as sample collection (e.g., same day as hERG assay).

journal_name

J Pharmacol Toxicol Methods

journal_title

Journal of pharmacological and toxicological methods

authors

Brimecombe JC,Kirsch GE,Brown AM

doi

10.1016/j.vascn.2008.10.004

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

29-34

issue

eissn

1056-8719

issn

1873-488X

pii

S1056-8719(08)00231-1

journal_volume

pub_type

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Test article concentrations in the hERG assay: losses through the perfusion, solubility and stability.