hERG Exposure Margin Calculator
Normalize hERG IC50 and high-clinical total/free Cmax to calculate exposure margins in parallel.
hERG exposure-margin results
Enter hERG potency and high-clinical-exposure inputs.
A margin is a comparison value, not a standalone safety decision. hERG and reference drugs require the same best-practice protocol; integrate measured exposure, assay variability, IC50 uncertainty, protein-binding uncertainty, metabolites, other ion channels, and in-vivo/clinical QT evidence.
Basis: ICH E14/S7B Q&A 1.2 — IC50/high clinical Cmax, free fraction, 1% floor, and parallel total/free review.
Tool Guide
Definition
hERG Exposure Margin Calculator — Normalizes hERG IC50 and nominal steady-state total Cmax to µM, applies a high-exposure multiplier and plasma fu, and calculates IC50/high total Cmax and IC50/high free Cmax. If fu<1%, an ICH E14/S7B Q&A sensitivity result using calculation fu=1% is displayed in parallel.
Purpose
(1) Normalize units for hERG IC50 and high clinical exposure (2) Cross-check total- and free-Cmax margins in parallel (3) Apply a high-exposure multiplier for DDI, organ impairment, or another scenario (4) Summarize conservative margins from an IC50 lower confidence bound
How to Use
① Enter the IC50 and optional lower 95% bound from a best-practice hERG assay. ② Enter nominal steady-state total Cmax, molecular weight, and plasma unbound percent. ③ Enter a high-exposure multiplier reflecting maximum therapeutic dose and intrinsic/extrinsic factors. ④ Compare total/free and point/lower-bound margins with reference drugs tested under the same protocol. No universal cutoff is embedded, and this tool alone does not determine TdP risk.
Examples
Example) hERG IC50=10 µM (lower bound 8), total Cmax=1,000 ng/mL, MW=500, fu=5%, high exposure=2× → nominal total Cmax=2 µM, high total=4 µM, high free=0.2 µM → point margins: total 2.5× and free 50× → lower-bound margins: total 2× and free 40× If fu=0.2%, the calculator also reports a calculation result using fu=1%.