Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites.

Atorvastatin is the most commonly used of all statins to lower cholesterol. Atorvastatin is extensively metabolized in both gut and liver to produce several active metabolites. The purpose of the present study is to develop a physiologically based pharmacokinetic (PBPK) model for atorvastatin and its two primary metabolites, 2-hydroxy-atorvastatin acid and atorvastatin lactone, using in vitro and in vivo data. The model was used to predict the pharmacokinetic profiles and drug-drug interaction (DDI) effect for atorvastatin and its metabolites in different DDI scenarios. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministration of atorvastatin with different medications such as itraconazole, clarithromycin, cimetidine, rifampin and phenytoin. This population based PBPK model was able to describe the concentration-time profiles of atorvastatin and its two metabolites reasonably well in the absence or presence of those drugs at different dose regimens. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC) values and between-phase ratios were in good agreement with clinically observed data. The model has also revealed the importance of different metabolic pathways on the disposition of atorvastatin metabolites. This PBPK model can be utilized to assess the safety and efficacy of atorvastatin in the clinic. This study demonstrated the feasibility of applying PBPK approach to predict the DDI potential of drugs undergoing complex metabolism.