Safety Pharmacology and Toxicological Testing

TABLE 22.2 Mechanistic Classes of Drugs Known to Perturb Cardiac Action Potential 

carried by the KvLQTl/minK channel blockers Chromanol 293B Inhibition of 1, reduces the cardiac repolarization reserve leading to prolongation of AP duration (false negative) Peng et al. (2010) Abassi et al. (2012) 

Cardiac sodium channel (NaVl.5) blockers Quinidine Inhibition of NaVl.5 current that governs the upstroke velocity of phase 0 of the cardiac AP significantly reduces the upstroke velocity and prolongs the AP duration, independent of hERG blockade (false negative) Roden and Hoffman (1985) Ducroq et al. (2007) 

Increase in cardiac sodium channel (NaVl.5) current Alfuzosin Delays cardiac repolarization by increasing sodium current leading to increased plateau potential and prolongation of AP duration and QT interval (false negative) Lacerda et al. (2008) Liang et al. (2013) 

Dual channel blockers Verapamil Verapamil-induced prolongation of AP duration due to its hERG blocking properties is negated by its inhibitory effect on cardiac calcium channels (false positive) Zhang et al. (1999) Redfem et al. (2003) 

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Before human clinical trials are initiated, a number of toxicology studies need to be completed and documented in the IND submission. In addition to the studies listed above for toxicology developability assessment, preclinical toxicology studies include local tolerance, genotoxicity, safety pharmacology, and subchronic tests. 

Safety concerns may arise from the presence of impurities or contaminants. It is preferable to rely on purification processes to remove impurities and contaminants rather than to establish a preclinical testing program for their qualification. In all cases, the product should be sufficiently characterized to allow an appropriate design of preclinical safety studies. In general, the product that is used in the definitive pharmacology and toxicology studies should be comparable to the product proposed for the initial clinical studies. (ICH S6)... 

The traditional method, used widely in nutrition, pharmacology, and toxicology, is to assume the equivalence between species of doses expressed as milligrams of test substance per kilogram of body weight. This method was adhered to by the Scientific Committee of the Food Safety Council and is implicit also in the traditional safety factor approach. 

Komiyama, BC, Y. Kawakubo, T. Fukushima, et al. 1977. Acute and subacute toxicity test on the extract from Glycyrrhiza. Oyo Yakuri 14(4) 535-548. Cited in Isbrucker, R.A., and G.A. Burdock. 2006. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyr-rhizin. Regul. Toxicol. Pharmacol. 46(3) 167-192. 

During precUnical development, several regulated studies are conducted those include, but are not limited to, safety pharmacology single-dose testing and repeat-dose testing in toxicology studies. These studies offer an opportunity to... 

The core battery of studies should be carried out before a substance is administered to humans for the first time. Any follow up or supplementary safety pharmacology studies should be carried out if there is a cause for concern raised from the toxicological battery of tests and / or from studies in humans. 

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