Controlled release (CR) formulations are usually designed to achieve similar exposure (AUC) levels as the\nmarketed immediate release (IR) formulation. However, the AUC is often lower following CR compared to\nIR formulations. There are a few exceptions when the CR formulations have shown higher AUC. This study\ninvestigated the impact of CR formulations on oral drug absorption and CYP3A4-mediated gut wall metabolism.\nA review of the current literature on relative bioavailability (Frel) between CR and IR formulations of\nCYP3A substrates was conducted. This was followed by a systematic analysis to assess the impact of the\nrelease characteristics and the drug-specific factors (including metabolism and permeability) on oral bioavailability\nemploying a physiologically-based pharmacokinetic (PBPK) modelling and simulation\napproach. From the literature review, only three CYP3A4 substrates showed higher Frel when formulated\nas CR. Several scenarios were investigated using the PBPK approach; in most of them, the oral absorption of\nCR formulations was lower as compared to the IR formulations. However, for highly permeable compounds\nthat were CYP3A4 substrates the reduction in absorption was compensated by an increase in\nthe fraction that escapes from first pass metabolism in the gut wall (FG), where the magnitude was dependent\non CYP3A4 affinity. The systematic simulations of various interplays between different parameters\ndemonstrated that BCS class 1 highly-cleared CYP3A4 substrates can display up to 220% higher relative\nbioavailability when formulated as CR compared to IR, in agreement with the observed data collected from\nthe literature. The results and methodology of this study can be employed during the formulation development\nprocess in order to optimize drug absorption, especially for CYP3A4 substrates.
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