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How much cardiac safety margin does this compound have?

hERG safety margin calculator

Compares the concentration at which a compound blocks half of the hERG channel, which helps keep the heart's rhythm, with the concentration free to act in the blood, and gives the ratio as a safety margin.

When to use itUse it during candidate selection, to compare arrhythmia (QT prolongation) risk across compounds or to judge whether more cardiac studies are needed.

Prefilled with an example: a hERG IC50 of 10 µM and a peak plasma concentration of 0.5 µM. Change any value and the result updates.

µM

The concentration at which the hERG assay showed half of the channel activity blocked. Use the same unit as the concentration below.

µM

The highest concentration in blood after dosing, including drug bound to proteins.

0–1

The share of drug free to move in the blood. Enter 0.1 for 10%.

Safety margin200 fold
Concentration free in the blood (free Cmax)0.05 µM

Blocking half the hERG current takes about 200 times the concentration free in the blood. That is above the commonly used 30-fold benchmark, so the cardiac concern reads as relatively low.

How to read it (this alone does not decide pass or fail)

The row that matches your result is marked.

  • 30-fold or moreYour resultAbove the benchmarkThe range where the risk of arrhythmia (torsade de pointes, TdP) is considered relatively low. Still, 30-fold is one benchmark and does not decide pass or fail by itself.
  • Below 30-foldBelow the benchmarkConsider further work, such as a study measuring the QT interval on the ECG in animals, and an integrated assessment that brings the results together.
  • For reference: known drugsMost drugs with no TdP reports in humans exceed 30-foldA benchmark from the comparison by Redfern et al. (2003). There are exceptions, such as verapamil (about 1.7-fold), that fall short of 30-fold with no reported problems.

How it is calculated

If you leave the fraction unbound at 1 (that is, use the total concentration), the margin comes out smaller than it really is for drugs that bind strongly to plasma proteins.

free Cmax = total Cmax × fraction unbound safety margin = hERG IC50 ÷ free Cmax

Source: The margin divides the hERG IC50 by the free Cmax. The approach comes from ICH S7B, the guideline on nonclinical evaluation of delayed ventricular repolarization.

With your numbers

  1. free Cmax = total Cmax × fraction unbound = 0.5 × 0.1 = 0.05 µM
  2. safety margin = hERG IC50 ÷ free Cmax = 10 ÷ 0.05 = 200-fold

Limits of this calculation

  • 30-fold is one benchmark, not a single pass criterion. The assessment assumes in vitro, animal and clinical results are considered together.
  • The IC50 changes with assay conditions (temperature, cells, protocol). Always use the same unit for the IC50 and the plasma concentration.
  • The reading depends on which concentration you use (plasma or tissue, and which species). Treat the result as an estimate for learning.

Primary sources

Every calculator gives an estimate for learning, built on published information and primary sources. Real decisions follow the applicable guidance and expert judgment.