Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are common disorders that can change the body's physiology and drugs pharmacokinetics. Solid dispersion (SD) preparation using supercritical fluid technology (SFT) has many advantages. Our study aimed to explore the effect of IBS and IBD on atorvastatin (ATV) pharmacokinetics, enhance ATV oral bioavailability (BCS II drug) using SFT, and analyze drug-disease-formulation interaction using a whole-body physiologically based pharmacokinetic (wbPBPK) model in rat and human. A novel ATV formulation was prepared using SFT and characterized in vitro and in vivo in healthy, IBS, and IBD rats. The resulting ATV plasma levels were analyzed using a combination of conventional and wbPBPK approaches. The novel formulation increased ATV solubility by 20-fold and resulted in a zero-order release of up to 95%. Both IBS and IBD increased ATV exposure after oral and intravenous administration by more than 30%. The novel SFT formulation increased ATV bioavailability by 28, 14, and 18% in control, IBD, and IBD rat groups and resulted in more consistent exposure as compared to raw ATV solution. Higher improvements in ATV bioavailability of more than 2-fold upon receiving the novel SFT formulation were predicted by the human wbPBPK model as compared to receiving the conventional tablets. Finally, the established wbPBPK model could describe ATV ADME in the presence of IBS and IBD after oral administration of raw ATV and using the novel SFT formula and can help scale the optimized ATV dosing regimens in the presence of IBS and IBD from rats to humans.
Keywords: in vitro binding and metabolism; inflammatory bowel disease; inflammatory bowel syndrome; soluplus-based formulation of atorvastatin using supercritical fluid technology; whole body physiologically based pharmacokinetics.
© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.