Simulation of Plasma Level Changes of Cerivastatin and Its Metabolites, Particularly Cerivastatin Lactone, Induced by Coadministration with CYP2C8 Inhibitor Gemfibrozil, CYP3A4 Inhibitor Itraconazole, or Both, Using the Metabolite-Linked Model

Background/Objective: This study investigates how drug-drug interactions (DDIs) with gemfibrozil (Gem), a potent CYP2C8 inhibitor, and itraconazole (Itr), a strong CYP3A4 inhibitor, affect the plasma levels of Cerivastatin (Cer) and its metabolites (M23, M1, and Cerivastatin lactone, Cer-L). The primary goal is to assess the risk of abnormal Cer-L elevation when Cer is co-administered with both Gem and Itr. Methods: We employed a newly developed Metabolite-Linked Model, which analyzes plasma metabolite levels by integrating the extent of formation (fM) and elimination rate (KeM) of both the parent drug and its metabolites. This model provides simultaneous analysis of Cer and its metabolites while determining the values for fM and KeM. Results: Simulated plasma concentrations of Cer and its metabolites in Cer + Gem and Cer + Itr DDIs matched observed data. The predicted area under the concentration-time curve ratios (AUCR) for Cer-L were 4.2 (Cer + Gem) and 2.1 (Cer + Itr), with KeM(+)/KeM ratios of 0.56 (Cer + Gem) and 0.53 (Cer + Itr), indicating elimination via CYP2C8 and CYP3A4, without involvement of other enzymes. In the Cer + Gem + Itr combination, the predicted AUCR for Cer-L was about 70, nearly seven times higher than the parent drug. Conclusions: These findings underscore the toxic risk associated with Cer, particularly due to fatal rhabdomyolysis when co-administered with both Gem and Itr, as a result of limited alternative pathways for Cer-L elimination. This pharmacokinetic model proves to be a valuable tool for as-sessing DDI risks and enhancing clinical drug development.