STANDARDIZATION OF SAFETY MARGIN

¹ From the Research Laboratories, Scientific Department, Hoffmann-La Roche, Inc., Nutley, N. J.

1. An improved standard for measuring the safety margin of drugs has been proposed. It is based on the determination of the dose-effect relationship, using suitable functions of dose and per cent effect. Statistical formulae necessary for making all calculations have been given.

2. Safety margin in the present concept is termed "Standard Safety Margin" and is defined as the zone between the surely effective dose (ED99) and the lowest lethal dose (LD1). It is expressed as a per cent of the ED99.

3. The "standard safety margin," calculated by the proposed method, lays increased emphasis on the actual zone of safety between the dose almost certain to be therapeutically effective and the dose likely to cause an occasional death.

4. Calculation of "standard safety margin" is made with the formula:

[See equation in the PDF file]

or by its logarithmic equivalent given in the text.

5. For allylisopropyl barbituric acid administered subcutaneously in the form of the sodium salt the ND50 in mice is 45 micrograms per gram body weight, and the LD50 is 237 micrograms per gram. The median therapeutic index is 5.24 and the standard safety margin 105 per cent.

6. For phenylethyl barbituric acid administered subcutaneously in the form of the sodium salt the ND50 in mice is 101 micrograms per gram, body weight, and the LD50 is 265 micrograms per gram. The median therapeutic index is 2.62 and the standard safety margin 34 per cent.