Cardiac Liability

Inhibition of cardiac ion channels can adversely affect heart function and negatively impact a drug’s probability of success, value and competitiveness.

Cardiac Liability1 1 | ApconiX
Cardiac Liability2 1 | ApconiX
Cardiac Liability3 1 | ApconiX

You will benefit from:

  • Access to ApconiX scientists who will tailor our service specifically to your needs and better advise you on your next steps
  • High quality ion channel profiling matched to your design-make-test cycle
  • An average turnaround time for hERG data of less than 4 days following receipt of customer compounds
Click here for more information or to discuss your specific requirements
ION Channel Screening Services

Our services include:

  • Ion channel screening for hERG, cardiac and neuro liabilities, and all elements of the CiPA paradigm including the ion channel panel (hERG, hNav1.5 peak and late current, hKvLQT1, hKv4.3, hCaV1.2, hKir2.1), in silico action potential modelling, and investigation in hiPSC-cardiomyocytes
  • Bespoke assay and cell line development
  • Expertly performed direct functional electrophysiology measurements with fewer artefacts than ligand-binding or fluorescence assays
  • Testing by manual patch-clamp or on the latest generation automated electrophysiology platforms (QPatch II and Patchliner) with the capacity for large numbers of compounds
Cardiac Liability4 | ApconiX
Cardiac Liability5 | ApconiX

Investigating Cardiac Liability

hERG Screening

By working with ApconiX you will benefit from our combined expertise in ion channel electrophysiology and project toxicology to move molecules away from this liability through informed choices in molecule design.

Our electrophysiology experts will rapidly generate high-quality hERG screening data for your drug discovery programme with an average turnaround time for hERG data of 4 days.

Here’s which ion channels are routinley screened in the pharma industry (Authier et al., 2017):

97% – hERG
60% – NaV1.5
55% – CaV1.2
37% – lks

NaV1.5 is cardiac sodium channel, CaV1.2 is cardiac “L-type” calcium channel, kvLQT1 is cardiac lks current

Refine your decision making with a deeper understanding of the potential for effects on cardiac safety to deliver an optimal and de-risked clinical candidate. ApconiX routinely offer sodium and calcium channel assays for a more comprehensive assessment of cardiac liability. On a case-by-case basis we can also deploy other cardiac ion channel assays to suit your needs including cardiac ‘T-type’ calcium channels and Kv1.5 as well as more advanced models of cardiac safety such as Purkinje fibre, cardiac contractility and Langendorf models.

It is a regulatory requirement that an assessment of hERG inhibition should be made by manual patch-clamp to Good Laboratory Practise (GLP) standards. GLP-hERG is provided through our expert partners.

Given over 500 years of combined expertise in drug discovery and safety, ApconiX is uniquely positioned to work with your project team to
interpret your data in the context of your drug discovery program.

Read our blog on hERG

Comprehensive in vitro Proarrhythmia Assay (CiPA)

The regulations regarding the testing of new drugs for cardiac safety are changing. ApconiX can help you understand how these new regulations will affect you and guide you through the testing process. We are working with a number of stakeholders to create this new regulatory framework called CiPA (Comprehensive in vitro Proarrhythmia Assay). The new paradigm will include the testing of a wider panel of ion channels, in silico modelling of ion channel data and measurements using human stem cell-derived cardiomyocytes.

ApconiX offers two critical experimental components of the CiPA assay package:

  • Ion channel testing of compounds against these cardiac ion channels: hERG, hNaV1.5 (peak current), hNaV1.5 (late current), hCaV1.2, hKir2.1, hKv4.3 (to current) and hKvLQT1/mink (Iks current)
  • Action potential measurement and proarrhythmia detection in human stem cell-derived cardiomyocytes

We continue to work with expert partners to provide in silico modelling and AP prediction.

We are always here to give you the advice you need to take an informed next step and we will support you to make the right decision.

Read our blog on CiPA
CiPA assay package | ApconiX
CiPA assay development | ApconiX
CiPA | ApconiX
CiPA-logo

ApconiX offers two critical experimental components of the CiPA assay package:

  • Ion channel testing of compounds against these cardiac ion channels: hERG, hNaV1.5 (peak current), hNaV1.5 (late current), hCaV1.2, hKir2.1, hKv4.3 (to current) and hKvLQT1/mink (Iks current)
  • Action potential measurement and proarrhythmia detection in human stem cell-derived cardiomyocytes

We continue to work with expert partners to provide in silico modelling and AP prediction.

We are always here to give you the advice you need to take an informed next step and we will support you to make the right decision.

Investigation of potential cardiotoxicity in hiPSC-cardiomyocytes using the Maestro Pro MEA assay system (Axion Biosystems).

The microelectrode array (MEA) in vitro cardiotoxicity assay measures the effect of compounds on action potential, field potential (FP), propagation and contractility. This data can be used to build a picture of compound cardiac liability before costly in vivo work.

Compound effect on action potential duration (APD, Figure 1a ) and changes in morphology are identified using local extracellular action potential assays (LEAP). This is a non-invasive tool allowing the visualisation of arrhythmias for example early after depolarisations (EAD’s, Figure 1b).

apconix cipa1 | ApconiX

Figure 1a. LEAP metrics measured under normal conditions and in the presence of increasing concentrations of Quinidine.

Quinidine addition (Na+ and K+ channel blocker) results in the prolongation of repolarisation giving rise to an increase in beat period and action potential duration.

| ApconiX

Figure 1b. LEAP measurements observed under normal conditions and in the presence of Quinidine

Quinidine at low dose causes a prolongation of repolarization, as the dose increases EAD’s are observed.

Flexibility and customer focus

Our clients may have known impurities in their test compound and need to understand the effect these may have in our assays. We are happy to investigate the effect of impurities in your preparations.

We also realise not all compounds are soluble in standard organic solvents, e.g. DMSO. Our clients are often looking for ways to increase the solubility of their compounds with a variety of organic and aqueous solvents. We are happy to try a number of solvents which have been validated in our assays.

Click here for more information or to discuss your specific requirements
| ApconiX

Ion Channel FAQs

The human ether-a-go-go related gene (hERG) encodes a cardiac potassium ion channel which controls the electrical activity of the heart and coordinates cardiac action potentials.

Because hERG plays such an important role in cardiac action potentials, inhibition of hERG function by drug compounds can cause heartbeat irregularity with potentially fatal consequences. Because of this, hERG screening is required for all new compounds to ensure they are safe for patients and volunteers.

Good laboratory practice (GLP) dictates that hERG testing is a regulatory requirement for all new compounds before they are administered to humans. Although there is no definitive time for hERG screening, sooner rather than later is always the best option while there is still opportunity to modify the chemistry of the compound and remove any liability or side effects before starting expensive preclinical studies.

Electrophysiology is the study of ions and the electrical currents they generate across biological cells, tissues and whole organ systems. In the drug development field, patch clamp electrophysiology is used to determine the normal function of a specific ion channel in a living cell and how its function can be modified by disease, genetic mutations or pharmaceutical intervention.

Electricity was long thought to be a separate entity from biology until the two were discovered to co-exist by Luigi Galvani in 1791 and his famous frog leg experiments. Over the next 150 years scientists continued to investigate the role electricity plays in biological tissues, and as our understanding grew, so did the field of electrophysiology itself as well as the technologies available to research bioelectricity. The patch clamp was first developed in the 1970s and paved the way for more detailed and experimental electrophysiology research. By the 1990s, researchers keen to speed up their electrophysiology experiments while keeping costs down began developing the automated patch clamp system which is widely in use today to gather electrophysiology data on individual cells more efficiently.

The best way to assess hERG activity is via functional hERG screening. Functional screening looks at the activity of the ion channel and provides information on the potency of the compound and therefore how much of a safety risk the compound is to cardiac function.

Binding screening simply looks at the binding of a compound to the hERG channel rather than at activity of the channel itself. Where binding hERG screening gives a binary yes or no answer to the question of ‘does the compound bind with hERG channels’, functional hERG screening quantifies the amount of hERG interaction with the compound giving a more detailed insight to the extent of hERG inhibition by the compound.

The IC50, or half maximal inhibitory concentration, measures how potently a compound inhibits a biological, electrophysiological or biochemical function. The hERG IC50 will depend on the compound being screened and the figure indicates the amount of drug needed to reduce hERG potassium channel function in vitro by 50%.

hERG safety margins are used to evaluate nonclinical cardiac safety by establishing how likely it is that a compound will cause potentially fatal cardiac arrhythmias known as Torsades de Pointes (TdP), or “twisting of the peaks”. Initial hERG safety margins for inducing TdP was set at a hERG IC50 value 30-fold above the therapeutic free plasma concentration (Webster, Leishman, & Walker, 2002) but it has since been suggested to aim for a hERG safety margin between 37- and 50-fold for TdP risk.

Thanks to advances in ion channel screening and development of automated patch clamp technology, ApconiX can turn hERG data around in an average of 4 days with CiPA screening taking an average of 14 days.

The Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative was developed by experts from industry, academia and regulatory authorities to facilitate a more sophisticated evaluation of a compound’s proarrhythmic potential. Rather than the one hERG ion channel, CiPA looks at seven ion channels that are involved in the different aspects of the cardiac action potential.

“Your data turnaround time is incredibly good and it really helps us track the SAR and progress our compounds in a rapid and efficient manner. Thanks ApconiX for your wonderful support to Bugworks.”

V Balasubramanian, Ph.D., Bugworks Research India Pvt. Ltd.

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