| Nobody working in drug development can fail to be | | | | The tests most commonly used are the hERG binding |
| aware of the issue that is QT prolongation, however | | | | assay and Rubidium flux tests |
| some people are finding they need a little more | | | | In terms of Ex-vivo models the most popular are |
| information if they are going to tackle and plan for it | | | | pukinji fiber tests and isolated heart tests, these |
| within their drug development programmes. | | | | whole tissue and whole organ tests are expensive |
| There are three main ways that cardiovascular | | | | but do provide a lot more information on what is |
| toxicity can present itself: | | | | going on and provide a wider insight. |
| | | | In-vivo tests include dogs, non-human-primates, and |
| 1. Changes to heart rate | | | | pigs, rodents are not a good model for the human |
| 2. Changes to conductivity within the heart | | | | heart and should not be used. Again the expense of |
| 3. Changes to the repolarization of the heart (QT | | | | these models is made up for by the excellent data |
| prolongation) | | | | they provide. The studies are generally conducted in |
| It is this QT prolongation that is obviously the | | | | conscious animals which are remotely monitored, |
| hottest issue and is a consequence of impacting the | | | | single dose cross over study designs are used, time |
| repolarization of the cardiomyocytes. The pathway is | | | | and duration of effect is looked for and compared |
| the hERG channels are blocked, which increased the | | | | with systemic drug levels. Heart rate, ECG, Blood |
| action potential of the cells in the heart, which in turn | | | | Pressure, Body Temperature, and activity levels are |
| causes the QT prolongation. | | | | all monitored. |
| This problem has been seen in a large number of | | | | One of the most important things to look at is left |
| drugs and has impacted on a great many drug | | | | ventricular pressure as this gives the greatest insight |
| development programmes, from complete removal | | | | into normal function, Charles Rivers have done a |
| of a drug from the market, to prescribing restrictions, | | | | great deal of work to validate this with Atenolo and |
| delays in approval and a huge number of drugs killed | | | | Pimobedam. With both drugs systolic BP, diastolic BP |
| at an early stage. It is also worth noting that there is | | | | and heart rate remained the same but changes in left |
| not a pattern to those drugs affected and it appears | | | | ventricular pressure alluded to issues that needed to |
| to affect a large number of different drugs. | | | | be addressed. |
| But what can be done to manage this risk? Well | | | | There are two guidelines that need to be referred to |
| there are a wide variety of early discovery screens, | | | | when planning these studies ICH57A (general safety |
| In-vitro, Ex-vivo, and In-vivo. | | | | pharmacology) and ICH57B (Specific QT prolongation |
| The most common In-vitro study is the Patch Clamp | | | | regulations). |
| - this is actually the gold standard study and involves | | | | When assessing the Pre-clinical it is important to take |
| measuring the current through the hERG channel (Ikr | | | | a good look at the data and consider the following; |
| Chanel) to give an IC50 for the drug, this IC50 will | | | | what was actually observed as the assays are not |
| give you an indication if you are going to see effects | | | | 100% effective, any small flags will impact on clinical |
| at therapeutic dose levels. Whilst this is the gold | | | | trial design, how will the expected PK/PD profiles |
| standard it is not a test that lends itself well to high | | | | impact on the results, will you expect patients to get |
| throughput screening. | | | | into affected dose levels? |
| Another test is the hERG binding assay, this is a | | | | Before commencing human trials there are guidelines |
| competitive assay that tests your drug against a | | | | that need to be considered ICH E14 which gives |
| radio labeled standard, this is a good test which can | | | | instruction on the evaluation of QT prolongation in |
| be used in high throughput screening, and is well | | | | man, in some regions its now compulsory, but in |
| correlated to the Patch Clamp test. | | | | others you can argue away from it with pre-clinical |
| Another is the Rubidium Flux assay, where you load | | | | data. In the clinic QT prolongation is tested in healthy |
| the cells with rubidium add your compound and KCl, | | | | volunteers at therapeutic doses and multiples thereof, |
| this allows you to measure the rubidium excreted | | | | metabolic inhibition may be needed to raise drug |
| from the cell and from this judge hERG channel | | | | levels levels high enough, positive controls are also |
| activity. This once again lends itself to even fast | | | | used (moxifloxacin). |
| screening but there is some drop off in relation to | | | | Where QT prolongation is seen the following |
| the gold standard. | | | | guidelines are provided: |
| The final test is the membrane potential dye test, | | | | - 6-10 msec unlikely risk |
| where cells are loaded with dye and as the hERG | | | | - >10 msec possible risk |
| channel functions dye is flushed from the cell, this is | | | | These regulations are the same for cardiovascular |
| the fastest test but least accurate. | | | | drugs as for other therapy areas. |