Cardiovascular Toxicity (QT Prolongation) In Drug Development Overview

Nobody working in drug development can fail to be aware of the issue that is QT prolongation, however some people are finding that they need a little more information if they are going to tackle and plan for it within their drug development programs.

There are three main ways that cardiovascular toxicity can present itself:

  1. Changes to heart rate
  2. Changes to conductivity within the heart
  3. Changes to the repolarization of the heart (QT prolongation)

It is this QT prolongation that is obviously the hottest issue and is a consequence of impacting the repolarization of the cardiomyocytes. The pathway is the hERG channels are blocked, which increased the action potential of the cells in the heart, which in turn causes the QT prolongation.

This problem has been seen in a large number of drugs and has impacted on a great many drug development programs, from complete removal of a drug from the market, to prescribing restrictions, delays in approval and a huge number of drugs killed at an early stage . It is also worth noting that there is not a pattern to those drugs affected and it appears to affect a large number of different drugs.

But what can be done to manage this risk? Well there are a wide variety of early detection screens, In-vitro, Ex-vivo, and In-vivo .

The most common In-vitro study is the Patch Clamp – this is actually the gold standard study and involves measuring the current through the hERG channel (Ikr Chanel) to give an IC50 for the drug, this IC50 will give you an indication if you are going to see effects at the therapeutic dose levels. Whilst this is the gold standard it is not a test that lends itself well to high throughput screening.

Another test is the hERG binding assay, this is a competitive assay that tests your drug against a radio labeled standard, this is a good test which can be used in high throughput screening, and is well correlated to the Patch Clamp test.

Another is the Rubidium Flux assay, where you load the cells with rubidium add your compound and KCl, this allows you to measure the rubidium excreted from the cell and from this judge hERG channel activity. This once again lends itself to even fast screening but there is some drop off in relation to the gold standard.

The final test is the membrane potential dye test, where cells are loaded with dye and as the hERG channel functions dye is flushed from the cell, this is the fastest test but least accurate.

The tests most commonly used are the hERG binding assay and Rubidium flux tests

In terms of Exvivo models the most popular are pukinji fiber tests and isolated heart tests, these whole tissue and whole organ tests are expensive but do provide a lot more information on what is going on and provide a greater insight.

In-vivo tests include dogs, non-human-primates, and pigs, rodents are not a good model for the human heart and should not be used. Again the expense of these models is made up for by the excellent data they provide. The studies are generally conducted in conscious animals which are remotely monitored, single dose cross over study designs are used, time and duration of effect is looked for and compared with systemic drug levels. Heart rate, ECG, Blood Pressure, Body Temperature, and activity levels are all monitored.

One of the most important things to look at is left ventricular pressure as this gives the greatest insight into normal function, Charles Rivers have done a great deal of work to validate this with Atenolo and Pimobedam. With both drugs systolic BP, diastolic BP and heart rate retained the same but changes in left ventricular pressure alluded to issues that needed to be addressed.

There are two guidelines that need to be referred to when planning these studies ICH57A (general safety pharmacology) and ICH57B (Specific QT prolongation regulations).

When assessing the Pre-clinical it is important to take a good look at the data and consider the following; what was actually observed as the assays are not 100% effective, any small flags will impact on clinical trial design, how will the expected PK / PD profiles affect on the results, will you expect patients to get into affected dose levels?

Before preceding human trials there are guidelines that need to be considered ICH E14 which gives instruction on the evaluation of QT prolongation in man, in some regions its now compulsory, but in others you can arguably away from it with pre-clinical data. In the clinic QT prolongation is tested in healthy volunteers at the therapeutic doses and multiples thereof, metabolic inhibiting may be needed to raise drug levels levels high enough, positive controls are also used (moxifloxacin).

Where QT prolongation is seen following the guidelines are provided:

  • 6-10 msec unlikely risk
  • > 10 msec possible risk

These regulations are the same for cardiovascular drugs as for other therapy areas.

Another important thing to consider is that QT prolongation is not an issue that affects biologicals, as demonstrated by Vergas, Boss et al. 2008 (J Pharmacol and Tox Method 58; 72-76)