Mechanistic PBPK Modeling of pH-Modifying Excipient Effects to Guide Formulation Design for Mitigating pH-Mediated...

pH-modifying acidic excipients (acidulants) or basic excipients are often used in drug formulations to improve solubility and chemical stability. In particular, acidulants are being increasingly employed as a mitigating strategy for pH-mediated drug-drug interactions (DDI) of basic drugs. The selection of these excipients and their doses has relied largely on empirical optimization, with limited use of physiologically based pharmacokinetic (PBPK) modeling. Published modeling efforts have focused on semimechanistic approaches such as manual adjustment of physiological gastrointestinal (GI) lumen pH or direct incorporation of in vitro dissolution profiles to recover observed pharmacokinetics (PK); however, these approaches may introduce uncertainty in prospective predictions when either drug or excipient quantities change. Thus, a mechanistic mathematical model based on first principles was developed and implemented in the Simcyp Simulator to predict the effects of these excipients on media pH (in vitro) or GI lumen pH (in vivo), which could in turn affect drug surface (microenvironment) pH and solubility. This model was used to predict the effect of the acidulants, tartaric acid and succinic acid, on both the in vitro dissolution and the clinical PK of two low-soluble weakly basic drugs, entrectinib and palbociclib. The model was able to predict the increase in in vitro dissolution rate when these excipients were used in the formulations. In clinical PK studies, the added acidulants were able to mitigate pH-mediated DDIs. The developed model recovered human PK with and without an acidulant in pH-DDI studies. Critical to these predictions was the ability of the model to not only predict the effect of excipients but also account for the self-buffering properties of ionizable drugs in the presence of buffers in vitro and in vivo. This study supports the model's utility in predicting the effectiveness of acidulants as pH-DDI mitigation strategies and informing formulation development.