PDE = (NOAEL x Weight Adjustment) / (F1 x F2 x F3 x F4 x F5)

The NOAEL is the highest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the NOAEL occurring at the lowest dose should be used for calculation of the PDE value. If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used. A NOAEL based on clinical

pharmacodynamic effects should correspond to the highest dose tested which is considered therapeutically inefficacious.

The PDE is derived by dividing the NOAEL for the critical effect by various adjustment factors (also referred to as safety-, uncertainty-, assessment- or modifying factors) to account for various uncertainties and to allow extrapolation to a reliable and robust no-effect level in the human or target animal population. F1 to F5 are addressing the following sources of uncertainty:

F1: A factor (values between 2 and 12) to account for extrapolation between species

F2: A factor of 10 to account for variability between individuals

F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks

F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity

F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

Pranjali Saxena

Thanks for your feedback!

That is, we do not need to change the formula for calculating the PDE for drugs for intranasal administration?

The challenge that the industry has not really dealt with is that the PDE is supposed to be for the material and should be independent of the route of administration. Better targeted formulations with much lower nominal doses are penalized, despite the fact that they likely have far fewer off-target effects. For example, the PDE for inhaled corticosteroids are much lower than oral steroids which carry far greater risks. The low PDE and OEL raises the bar with regards to exposure requirements during manufacturing even though a specialized device is needed to achieve the targeted dose. This is a big problem...