Developability assessment of clinical drug products with maximum absorbable doses

Maximum absorbable dose refers to the maximum amount of an orally administered drug that can be absorbed in the gastrointestinal tract. Maximum absorbable dose, or Dabs, has proved to be an important parameter for quantifying the absorption potential of drug candidates. The purpose of this work is to validate the use of Dabs in a developability assessment context, and to establish appropriate protocol and interpretation criteria for this application. Three methods for calculating Dabs were compared by assessing how well the methods predicted the absorption limit for a set of real clinical candidates. Dabs was calculated for these clinical candidates by means of a simple equation and two computer simulation programs, GastroPlus™ and an program developed at Eli Lilly and Company. Results from single dose escalation studies in Phase I clinical trials were analyzed to identify the maximum absorbable doses for these compounds. Compared to the clinical results, the equation and both simulation programs provide conservative estimates of Dabs, but in general Dabs from the computer simulations are more accurate, which may find obvious advantage for the simulations in developability assessment. Computer simulations also revealed the complex behavior associated with absorption saturation and suggested in most cases that the Dabs limit is not likely to be achieved in a typical clinical dose range. On the basis of the validation findings, an approach is proposed for assessing absorption potential, and best practices are discussed for the use of Dabs estimates to inform clinical formulation development strategies.

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