Abstract:
: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 D(abs), 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 D(abs) in a developability assessment context, and to establish appropriate protocol and interpretation criteria for this application. Three methods for calculating D(abs) were compared by assessing how well the methods predicted the absorption limit for a set of real clinical candidates. D(abs) 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 D(abs), but in general D(abs) 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 D(abs) 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 D(abs) estimates to inform clinical formulation development strategies.
journal_name
Int J Pharmjournal_title
International journal of pharmaceuticsauthors
Ding X,Rose JP,Van Gelder Jdoi
10.1016/j.ijpharm.2012.02.003subject
Has Abstractpub_date
2012-05-10 00:00:00pages
260-9issue
2eissn
0378-5173issn
1873-3476pii
S0378-5173(12)00136-6journal_volume
427pub_type
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