AAPS Webinar: Translating manufacturing variants from in vitro to the clinic. Opportunities and gaps for IR formulations with additional IVIVC ‘Safe Space’ applications

Authors: Mullin JM
Division: Simulations Plus


Development of an in vitro/in vivo correlation (IVIVC) can be most challenging for immediate release (IR) products.  Quite often, the dissolution prediction of drug products may not always follow traditional Noyes-Whitney models based on particle size.  Granulation and tableting processes may cause drug product dissolution to be limited by excipients, tablet hardness, granule size, etc.  A modeling approach gaining in popularity, the Z-factor dissolution model, provides the ability to use biorelevant dissolution data measured at multiple pH and/or bile concentrations to extract dissolution rate rather than rely on theoretical predictions1.  In this webinar, a case study for Galunisertib will be presented using Z-factor dissolution rates were initially calculated in different buffer systems from pH 2-6.8 in USP2 dissolution apparatus.  Additionally, an in vitro simulation model for the artificial stomach duodenum (ASD) experiment in DDDPlus™ was used to determine the Z-factor dissolution rate and precipitation time for Galunisertib from biorelevant in vitro data.  The in vitro dissolution rates and precipitation times were then used to predict and validate in vivo pharmacokinetics in GastroPlus® using a full physiologically based pharmacokinetic (PBPK) model.  With the validated model, a novel IVIVC was built to connect the in vitro Z-factor dissolution to the deconvoluted in vivo dissolution rates.  The approach performed much better than traditional methods like Loo-Riegelman or the more advanced GastroPlus mechanistic deconvolution.   We will also review applications of mechanistic IVIVC for extended release (ER) formulations and highlight applications of DDDPlus and GastroPlus to determine dissolution and excipient bioequivalence safe space.

By Jim Mullin