In Vitro Therapeutic Indices

When pharmacology targets and homologous or nonhomologous secondary off-targets are molecularly well defined, the temptation to calculate ratios of IC50s at desired efficacy endpoints to safety endpoints leads to the creation of in vitro therapeutic indicest Typically, these are large numbers that lull many a discovery working group into a false sense of security. Two examples are provided based on real outcomes, for which large in vitro ratios would potentially create an illusion of greater safety. For example, an oncology compound had a hERG (Ikr; repolorizing K' current) ICt0 value of 35 |M and a target receptor IC50 value of 10 nM, ostensibly providing a 3500-fold safety window.

Caveats for the use of these simple formulas are:

• Plasma protein binding if pharmacologic or toxicologic activity relates to the free fraction

• Relative concentration in tissue may exceed plasma by many fold

• Tissue - bound drug, and thus tissue concentration at efficacy and toxicity targets can be difficult to determine and may influence the expression of efficacy or toxicity

• Typically, one uses IC50 values for ion channels, although inhibition of hERG at an IC1 0 may still produce clinically important prolongation in the QT interval

• The efficacy and toxicity of metabolites

After integrating these various considerations to the calculation of a safety margin, and considering the simple unknown, which is the biological counter part to in vitro activity when measured in vivo, the safety margins for QT prolongation due to hERG inhibition were in the five to tenfold range.

In a second example, a compound with IC50 for phosphodiesterase (PDE4) intravenously of 2|M was considered safe for a central nervous system efficacy target with EC50 of 1000-fold less (2 nM). At the lowest dosage tested in animals, projected to provide a threefold safety multiple, portal vasculitis was observed in rodents, considered likely to be secondary to PDE4 inhibition at a plasma Cmax of only 70 nM. This toxicity is generally driven by Cmax . and as peak concentrations occur in the portal vasculature during absorption of drug from the small intestine, the potential toxicity can be markedly exaggerated relative to in vitro determined safety windows.

Frequently, the exposure-response relationship for in vitro surrogates of in vivo toxicity can be quite poor. Although this makes prediction of valid safety windows difficult, in vitro-determined numbers are still valuable in permitting the rank ordering of compounds within a chemical series for selection, and for refining in vivo assessments.

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