pH-stat versus pH-shift lipolysis model: Exploring in vitro-in vivo relationships for lipid-based formulations of nilotinib

Abstract

The pH-stat in vitro lipolysis method is well established for evaluating lipid-based formulations (LBFs), however the absence of a simulated gastrointestinal transition may lead to an overestimation of drug precipitation particularly in the case of weakly basic drugs. This study aimed to compare the conventional pH-stat method with a pH-shift lipolysis approach by evaluating a diverse set of LBFs using nilotinib, a weakly basic model drug. Additionally, the study sought to assess in vitro–in vivo relationships (IVIVRs) and enhance understanding of the predictive capabilities of these models. Four nilotinib-containing LBFs were tested in vitro, and pharmacokinetic profiles were evaluated in Sprague Dawley rats. The formulations included a supersaturated Peceol® solution (sLBF), a Peceol® lipid suspension (type I according to the Lipid Formulation Classification System (LFCS)), a type III LFCS medium-chain suspension, and a type IV LFCS suspension. The highest bioavailability was achieved with the Peceol® sLBF and the type III LFCS formulation. Strong IVIVRs were established for both in vitro lipolysis models. In conclusion, utilizing both in vitro models offered distinct advantages depending on the stage of development and the specific questions being addressed. This approach contributes to more efficient formulation development and a reduced reliance on animal studies in early-stage drug development.