hERG inhibition leading to cardiac toxicity

Support for Essentiality of KEs

Defining Question

High (Strong)

Moderate

Low (Weak)

Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Direct evidence from experimental studies illustrating essentiality for at least one of the important KEs.

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE.

No or contradictory experimental evidence of the essentiality of any of the KEs.

KE1:

Direct hERG Channel Blockage

Strong

The human ether-a-go-go related gene (hERG) or KCNH2 gene encodes a voltage-gated potassium channel known as the hERG channel. This channel plays a key role in cardiac action potential repolarization. Reduced function of hERG causes potential action prolongation and increases the risk for potentially fatal ventricular arrhythmia, torsades de pointes [1].

KE2:

Induction of hERG trafficking defect

Strong

Prolongation of the AP can result from decreased inactivation of the inward Na+ or Ca++ currents, increased activation of the Ca++ current, inhibition of one or more of the outward K+ currents or altered potassium channel trafficking and protein synthesis [2].

KE3:

Inhibition of Ikr

Strong

Consequences of IKr blockade that may combine to facilitate TdP arrhythmia.AP (action potential) prolongation is a proximate effect of IKr blockade at the cellular level and in the ECG is reflected by QT interval (QTi) prolongation [3].

K4:

Prolongation of Action Potential

Strong

Inhibition of hERG channels tends to lengthen the cardiac action potential and the duration from the start of the the QRS complex to the end of the T wave in the electrocardiogram (QTinterval) [4].

KE5:

Prolongation of QT interval

Strong

Drug-induced QT prolongation leading to serious ventricular arrhythmias, such as torsade de pointes (TdP), poses a major safety consideration for the development and use of new drug candidates. TdP is always associated with prolongation of the QT interval of the surface ECG [5].

KE6:

Torsade de Pointes

Strong

Long QT syndrome (LQTS), an abnormality of cardiac muscle repolarization that is characterized by the prolongation of the QT interval in the electrocardiogram, was implicated as a predisposing factor for torsades de pointes, a polymorphic ventricular tachycardia that can spontaneously degenerate to ventricular fibrillation and cause sudden death [6].

Support for Biological Plausibility of KERs

MIE1 to KE1

Binding to hERG channel leads to Direct hERG channel blockage

Biological Plausibility of the MIE1 => KE1 is STRONG.

Abnormal cardiac electrical activity is most often a side effect from unintended block of the promiscuous drug target the human ether-à-go-go-related gene (hERG)— the delayed rectifier K+ channel in the heart. Numerous drugs interact with the promiscuous target hERG [7].

Many drugs covering a broad spectrum of pharmaceutical classes have been withdrawn from the market or have had their usage limited due to blockage of the hERG, e.g., astemizole, terfenadine, cisapride, sertindole, terolidine, droperidol, lidoflazine, and grepafloxacin [8].

MIE2 to KE2

hERG channel biogenesis interference leads to Induction of hERG trafficking defects

Biological Plausibility of the MIE2 => KE2 is STRONG.

There are drugs such as probucol, fluoxetine, arsenic, and pentamidine,

which do not block hERG channels but are torsadogenic due to abnormal potassium channel protein synthesis or trafficking [2].

In addition to direct hERG channel block, multiple pharmacological agents can cause hERG deficiency (with hERG channel block or independently) by the inhibition of its biogenesis and trafficking [9].

Several therapeutic compounds have been identified that reduce hERG/IKr currents not by direct block but by inhibition of hERG/IKr trafficking to the cell surface [10].

KE1 to KE3

Direct hERG channel blockage leads to Inhibition of Ikr

Biological Plausibility of the KE1 => KE3 is STRONG.

Some antagonists of the H1 histamine receptor, such as astemizole and terfenadine, which belong to the second generation (i.e. are devoid of sedative effects), can block the HERG channel, causing a decrease in the IKr current [11].

The Kv11.1 channel, a voltage-gated potassium channel previously known as human ether-à-go-go related gene (hERG), encodes the pore-forming subunit of the rapid component of the delayed rectifier K+ channel, IKr, which contributes to phase 3 repolarization in cardiac action potentials [12].

KE2 to KE3

Induction of hERG trafficking defects leads to Inhibition of Ikr

Biological Plausibility of the KE2 => KE3 is STRONG.

There are several types of cardiac K+ channels in the heart that are responsible for different phases of the action potential. Three of them are involved in (late) repolarization. One of these channels, known as hERG (human ethera-go-go-related gene,254 or Kv11.1 or KCNH2, the latter is the name of the gene) is extremely sensitive to inhibition by many compounds. It mediates the so-called rapid component of the delayed rectifier current (IKr current). If this current is suppressed, repolarization is slowed and QT interval prolongation is observed in the ECG. Because the synthesis of the hERG channels is particularly complicated, the IKr current can be suppressed not only by direct inhibition of the hERG  , but also by any interference in their synthesis and/or intracellular trafficking [13].

KE3 to KE4

Inhibition of Ikr leads to Prolongation of Action Potential

Biological Plausibility of the KE3 => KE4 is STRONG.

hERG encodes a voltage-gated potassium channel which is a key component in formation of the cardiac action potential. This channel carries delayed rectifying potassium current (IKr) which underlies repolarization of the cardiac action potential. Pharmacological blockade of the hERG channel results in a slowing of repolarization of the action potential which is reflected as a prolongation of action potential duration [14].

Rapidly activating K current (IKr) blockers prolong action potential (AP) duration (APD) in a reverse-frequency-dependent manner [15].

Virtually every case of a prolonged duration of cardiac action potential related to drug exposure (acquired LQTS) can be traced to one specific mechanism: blockade of IKr current in the heart [16].

KE4 to KE5

Prolongation of Action Potential leads to Prolongation of QT interval

Biological Plausibility of the KE4 => KE5 is STRONG.

Rationale

The acquired long QT syndrome is both a threat to public health and a major stumbling block for drug development. It is most often caused through unintended blockade of the cardiac repolarizing potassium channel, IKr, encoded by the Human Ether-a-go-go related gene (hERG). Blockade of hERG channel was found to be associated with an increased duration of ventricular repolarization and prolongation of QT interval (long QT syndrome, or LQTS) [17].

There are several types of cardiac K+ channels in the heart that are responsible for different phases of the action potential. Three of them are involved in (late) repolarization. One of these channels, known as hERG (human ethera-go-go-related gene,254 or Kv11.1 or KCNH2, the latter is the name of the gene) is extremely sensitive to inhibition by many compounds. It mediates the so-called rapid component of the delayed rectifier current (IKr current). If this current is suppressed, repolarization is slowed and QT interval prolongation is observed in the ECG [13].

KE5 to KE6

Prolongation of QT interval leads to Torsade de Pointes

Biological Plausibility of the KE5 => KE6 is STRONG.

The human ether-a-go-go related gene (hERG) or KCNH2 gene encodes a voltage-gated potassium channel known as the hERG channel. This channel plays a key role in cardiac action potential repolarization. Reduced function of hERG causes potential action prolongation and increases the risk for potentially fatal ventricular arrhythmia, torsades de pointes [1].

The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk [18].

Drug-induced QT prolongation leading to serious ventricular arrhythmias, such as torsade de pointes (TdP), poses a major safety consideration for the development and use of new drug candidates [5].

KE6 to AO

Torsade de Pointes leads to Sudden cardiac death

Biological Plausibility of the KE6 => AO is STRONG.

Human hereditary long QT syndrome (LQTS) is a heterogeneous cardiac disorder characterized by a prolonged QT interval on the surface ECG and an increased risk for sudden cardiac death due to life-threatening ‘‘torsade de pointes’’ arrhythmias [19].

The importance of hERG (human ether-a-go-go-related gene1) K channels in normal human cardiac electrical activity became strikingly obvious when inherited mutations in HERG were found to cause long QT syndrome (LQTS)2, a cardiac repolarization disorder that predisposes affected individuals to arrhythmia (rapid irregular heart beats that can lead to fainting and sudden death) [20].

Empirical Support for KERs

Defining Question

High (Strong)

Moderate

Low (Weak)

Does empirical evidence support that a change in KEup leads to an appropriate change in KEdown? Does KEup occur at lower doses, earlier time points, and higher in incidence than KEdown ? Inconsistencies?

Multiple studies showing dependent change in both events following exposure to a wide range of specific stressors. No or few critical data gaps or conflicting data.

Demonstrated dependent change in both events following exposure to a small number of stressors. Some inconsistencies with expected pattern that can be explained by various factors.

Limited or no studies reporting dependent change in both events following exposure to a specific stressor; and/or significant inconsistencies in empirical support across taxa and species

MIE1 => KE1

High

Abnormal cardiac electrical activity is most often a side effect from unintended block of the promiscuous drug target the human ether-à-go-go-related gene (hERG)—the delayed rectifier K+ channel in the heart [7].

MIE2 => KE2

High

In addition to direct hERG channel block, multiple pharmacological agents can cause hERG deficiency (with hERG channel block or independently) by the inhibition of its biogenesis and trafficking [9].

KE1 & KE2 => KE3

High

There are several types of cardiac K+ channels in the heart that are responsible for different phases of the action potential. Three of them are involved in (late) repolarization. One of these channels, known as hERG (human ethera-go-go-related gene,254 or Kv11.1 or KCNH2, the latter is the name of the gene) is extremely sensitive to inhibition by many compounds. It mediates the so-called rapid component of the delayed rectifier current (IKr current). Most drugs that cause QT interval prolongation are direct inhibitors of the channel, but there are many compounds that block their synthesis/trafficking or interfere at both levels [13].

KE3 => KE4

Moderate

Since almost all compounds that produce TdP in man also inhibit the rapid form of the delayed rectifier potassium current IKr, encoded by the hERG gene, the blockade of this channel and derived electrophysiological consequences on the cellular level including prolongation of action potential duration (APD) [21].

Inhibition of the hERG channel does not always translate into APD prolongation. Martin et al. (2004) investigated the APD prolonging potential of ten hERG blockers in the canine Purkinje fiber model. Only four compounds demonstrated convincing monotonic concentration-dependent APD prolongation. Comparable levels of hERG block did not result in the same APD prolongation [22].

KE4 => KE5

High

The QT interval of the human electrocardiogram (ECG) is a marker of the duration of the cellular action potential (AP) [23].

Loss of hERG function is associated with long-QT syndrome type-2 (LQT2), characterized by impaired ventricular repolarization, extended action potential duration and increased risk of potentially fatal torsades de pointes arrhythmia [24].

KE5 => KE6

Low

Prolongation of the QT interval in telemetered dogs and primates has a high predictive value for QT interval prolongation in man (ILSI workshop ‘‘Cardiovascular Risk Assessment’’, Washington June 3–4, 2003). But accumulating evidence suggests that only a weak correlation exists between QT prolongation and TdP in humans [21].

Although QT prolongation is an essentialfirst stepin  TdP,  it  is  usually  not  considered  sufficient  toinduce TdP [25].

KE6 => AO

Low

Around 50% of patients with Torsades de Pointes are asymptomatic. The most common symptoms reported are syncope, palpitations, and dizziness. However, cardiac death is the presenting symptom in up to 10% of patients [26].

The administration of an IKr current blocking agent may  significantly prolong the QT interval in these silent carriers predisposing them to TdP and sudden cardiac death [27].