An in silico physiologically-based pharmacokinetic (PBPK) study of the impact of the drug release rate on oral absorption, gut wall metabolism and relative bioavailability
Andrés Olivares-Morales (1), Adam S. Darwich (1), Yoshiteru Kamiyama (1, 2), Leon Aarons (1) and Amin Rostami-Hodjegan (1, 3).
(1) Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK. (2) Discovery Drug Metabolism & Pharmacokinetics, Analysis & Pharmacokinetics Labs., Astellas Pharma Inc., Ibaraki, Japan.(3) Simcyp Limited, Blades Enterprise Centre, Sheffield, UK
Objectives: To investigate the impact of the drug release rate on oral drug absorption and CYP3A4-mediated gut wall metabolism and to identify the formulation and drug-specific factors associated with higher relative bioavailability observed for some controlled release (CR) formulations compared to their immediate release (IR) counterparts [1,2].
Methods:A systematic analysis was performed to assess the impact of formulation characteristics and drug-specific factors on oral bioavailability. A set of virtual compounds were generated by combinations of different values for drug-related parameters such as: aqueous solubility, human jejunal effective permeability (Peff), maximal CYP3A4-mediated metabolic rate (Vmax, CYP3A4), CYP3A4 affinity (Km, CYP3A4) maximal P-gp-mediated efflux rate (Jmax, P-gp) and P-gp affinity (Km, P-gp). Five different release profiles were evaluated for each virtual compound, from fast (IR) to slow release (CR). Simulations were performed employing the “Advanced Dissolution Absorption and Metabolism (ADAM)” model within the Simcyp® Population-Based Simulator (v12) . The results were analyzed for trends in fraction of the drug absorbed (fa), fraction that escapes from first pass metabolism in the gut wall (FG) and relative oral bioavailability (Frel).
Results:In all the investigated scenarios the oral absorption (fa) 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 FG, which was dependent on CYP3A4 affinity. In addition, BCS class 1 highly-cleared CYP3A4 substrates displayed up to 220% higher Frel when formulated as CR compared to their IR formulations.
Conclusions:The results were consistent with a previous study on the colonic absorption of several drugs. This study gives a mechanistic insight in to the processes involved in the absorption and first pass metabolism in the distal regions of the GI tract. The decreased absorption in the distal regions of the GI tract can be compensated by a reduction of the intestinal first pass metabolism, presumably due to the distribution of the CYP3A enzymes along the gut wall, where the abundance in to the distal regions is decreased compared to that in the upper regions. This information can be employed during the formulation development in order to maximize drug absorption, especially for CYP3A4 substrates.
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