Integrated Physiologically-based Pharmacokinetic Model with a Quantitative Systems Pharmacology and Toxicology Model for Statins in Disease Population. Part 2: MIDD and MIPD Applications.

The conventional strategy of prescribing the same dosage to all patients can result in suboptimal efficacy and safety. This is particularly true when considering drug-gene interactions (DGIs), drug-drug interactions (DDIs), or in individuals with compromised organ function. Precision medicine, which aims to tailor drug regimens based on individual patient characteristics, offers a promising alternative by focusing on drug disposition, efficacy, and safety. However, clinical trials face ethical and practical challenges and cannot cover all real-world patient scenarios. Thus, physiological based pharmacokinetic (PBPK) modeling offers a unique framework for enhancing model-informed drug development (MIDD) and precision dosing (MIPD). Despite this, most PBPK applications primarily assess drug pharmacokinetics without evaluating efficacy or safety outcomes. This limits the full potential of mechanistic models. In this study we used integrated PBPK, Quantitative Systems Pharmacology (QSP), and toxicology models to predict risks in scenarios like DGIs, DDIs, and varied renal impairment by simultaneously assessing drug PK, pharmacological effect, and toxicity. The findings underscore the importance of considering pharmacological effects and myotoxicity risks, which differed from changes seen in plasma exposure. This study demonstrates the value of PBPK-QSP models in guiding dose adjustments to optimize the efficacy and safety balance in target patient populations, showcasing their strength in MIDD and MIPD strategies.