Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model

Abstract

Controlled release (CR) formulations are usually designed to achieve similar exposure (AUC) levels as the marketed immediate release (IR) formulation. However, the AUC is often lower following CR compared to IR formulations. There are a few exceptions when the CR formulations have shown higher AUC. This study investigated the impact of CR formulations on oral drug absorption and CYP3A4-mediated gut wall metabolism. A review of the current literature on relative bioavailability (Frel) between CR and IR formulations of CYP3A substrates was conducted. This was followed by a systematic analysis to assess the impact of the release characteristics and the drug-specific factors (including metabolism and permeability) on oral bioavailability employing a physiologically-based pharmacokinetic (PBPK) modelling and simulation approach. From the literature review, only three CYP3A4 substrates showed higher Frel when formulated as CR. Several scenarios were investigated using the PBPK approach; in most of them, the oral absorption of CR formulations was lower as compared to the IR formulations. However, for highly permeable compounds that were CYP3A4 substrates the reduction in absorption was compensated by an increase in the fraction that escapes from first pass metabolism in the gut wall (FG), where the magnitude was dependent on CYP3A4 affinity. The systematic simulations of various interplays between different parameters demonstrated that BCS class 1 highly-cleared CYP3A4 substrates can display up to 220% higher relative bioavailability when formulated as CR compared to IR, in agreement with the observed data collected from the literature. The results and methodology of this study can be employed during the formulation development process in order to optimize drug absorption, especially for CYP3A4 substrates.

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

“…Whereas some drugs have been successfully modelled using jejunal P eff (i.e. M1) as a fixed value along all the GI segments within the PBPK model (72), others might not necessarily benefit from such an approach, due to the inherent risk of overestimations in the f abs , especially for lowly permeable drugs (73). Thus, the use of P reff int seems to be an appropriate alternative during the bottom-up prediction of oral absorption of drugs administered as MR or at least a good starting point (Fig.…”

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

“…By employing this approach, we were able to evaluate the interplay between drug and physiological-related factors governing intestinal absorption and first-pass metabolism, and in particular to identify the possible scenarios where MR formulations of a CYP3A substrate might display higher relative bioavailability (F rel ) compared to its immediate released (IR) counterparts (21). In our previous study, it was shown that highly cleared CYP3A-substrates belonging to Class 1 within the biopharmaceutics classification system (BCS) are more likely to display higher F rel when formulated as MR (21). The mechanism proposed for this phenomenon is an increased intestinal availability (F G ) due to a decreased intestinal first-pass metabolism as a result of the lower abundance of CYP3A enzymes in the distal gastrointestinal (GI) tract, where most of the drug contained in the MR formulation is likely to be released and absorbed (21)(22)(23)(24).…”

“…The mechanism proposed for this phenomenon is an increased intestinal availability (F G ) due to a decreased intestinal first-pass metabolism as a result of the lower abundance of CYP3A enzymes in the distal gastrointestinal (GI) tract, where most of the drug contained in the MR formulation is likely to be released and absorbed (21)(22)(23)(24). Another interesting outcome of the study was the observed trend to over predict f abs of MR formulations belonging to BCS Classes 2 and 3 (21,25). This over prediction was attributed to an overestimation of the colonic absorption due to the PBPK approach employed for the study.…”

“…In our previous study, it was shown that highly cleared CYP3A-substrates belonging to Class 1 within the biopharmaceutics classification system (BCS) are more likely to display higher F rel when formulated as MR (21). The mechanism proposed for this phenomenon is an increased intestinal availability (F G ) due to a decreased intestinal first-pass metabolism as a result of the lower abundance of CYP3A enzymes in the distal gastrointestinal (GI) tract, where most of the drug contained in the MR formulation is likely to be released and absorbed (21)(22)(23)(24). Another interesting outcome of the study was the observed trend to over predict f abs of MR formulations belonging to BCS Classes 2 and 3 (21,25).…”

“…In a recent study, we investigated the impact that modified/controlled release (MR/ CR) formulations might have on the oral bioavailability of substrates of the cytochrome P450 (CYP) 3A4 enzymes using a prospective PBPK modelling and simulation (M&S) approach (21). By employing this approach, we were able to evaluate the interplay between drug and physiological-related factors governing intestinal absorption and first-pass metabolism, and in particular to identify the possible scenarios where MR formulations of a CYP3A substrate might display higher relative bioavailability (F rel ) compared to its immediate released (IR) counterparts (21). In our previous study, it was shown that highly cleared CYP3A-substrates belonging to Class 1 within the biopharmaceutics classification system (BCS) are more likely to display higher F rel when formulated as MR (21).…”