Drug Development
The fall in R&D productivity corresponds with the pharmaceutical industry’s focus on creating new therapeutic targets that will have less post-launch competition. The drawback of this approach, how- ever, is the difficulty in developing such drug can- didates with high efficacy and low safety risk. Due to this, the approach tends to come with lower suc- cess rates yet higher development costs. Why aren’t these innovative drug candidates meeting safety requirements? A review of drug development data6 shows that cardiovascular tox- icity is often to blame, accounting for approxi- mately 27% of drug failures due to toxicity in the preclinical phase. Phase I clinical studies are rela- tively safer in terms of cardiovascular toxicity, with only 9% showing serious adverse drug reactions. The overall attrition rate due to cardiovascular events in clinical development is 21%, indicating that several cardiovascular effects occur in Phase II and III clinical trials which are not detected in the preclinical studies or earlier clinical trials6. There are several different types of cardiovascular toxici- ty; one major type is toxicity caused by drug effects on cardiac ion channels like hERG.
It’s all about hERG: the human Ether-à-go-go Related Gene (hERG) ion channel
The sum of the action potentials of the different parts of the heart is clinically monitored using sur- face electrodes and results in an electrocardiogram, or ECG. Drugs that affect ion channels in the heart can change ECG parameters such as the QT-inter- val, which represents the time from the depolarisa- tion of the ventricles to the repolarisation of the ventricles. Many drugs showing cardiac toxicity prolong the QT-interval in the ECG6,7. Drug- induced prolongation of the QT-interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia that can cause sudden cardiac death. Drugs prolonging the QT interval appear to con- sistently inhibit the outward, rapid-delayed rectifi- er K+ current (IKr) conveyed by the hERG (human Ether-à-go-go Related Gene, or the KCNH2 gene in the modern nomenclature) channel. Therefore an in vitro study to assess a compound’s potential to inhibit this channel is an essential part of the non-clinical regulatory testing battery. The hERG gene encodes for the pore-forming subunit of the voltage-gated potassium (K+) channel that controls the outward potassium current during a cardiac contraction. The hERG ion channel has long been known to be the target of class III anti-arrhythmic drugs such as amiodarone. Unfortunately, the hERG channel also interacts with a variety of non-
Drug Discovery World Spring 2013
cardiovascular drugs. Several drugs, in fact, have been withdrawn from the market due to adverse cardiac effects. Examples include astemizole, an antihistamine, and cisapride, a gastroprokinetic drug7. As a result, a direct assay of hERG channel inhibition is now an expected part of the safety pharmacology package conducted to support initi- ation of First-in-Man clinical trials.
Regulatory studies for non-clinical cardiovascu- lar safety testing are described in the ICH guide- lines S7A and S7B. ICH S7A describes safety Pharmacology Studies for Human Pharmaceuticals. ICH S7B extends and comple- ments this guideline and describes studies for the assessment of QT-interval prolongation. Studies described in the ICH S7B guideline identify the potential of a test substance and its metabolites to delay ventricular repolarisation (QT-prolonga- tion), and assess the dose relationship between the compound concentration and the effect.
The manual patch clamp technique: the current standard Today’s standard for measuring hERG inhibition is the manual patch clamp technique. Through this technique, a cell present in a bath is approached with a glass pipette containing an electrode by using a micromanipulator. The prin- ciple of the manual patch clamp technique is shown in the upper part of Figure 2. During this
61 Figure 1
The automated patch clamp platform CytoPatch
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