Integrated Physiologically-Based Pharmacokinetic Model with a Quantitative Systems Pharmacology and Toxicology Model...

It is important to understand the key factors affecting the pharmacokinetics (PK), pharmacological response and toxicity of a drug to ensure clinical therapeutic efficacy and safety across disease populations. Traditionally, label dose-adjustment recommendations for patient populations are based on drug plasma concentrations. However, plasma PK may not be an appropriate surrogate for response and/or toxicity for drugs like statins with intracellular targets and tissue distribution influenced by membrane transporters. This study presents the integration of a physiologically-based pharmacokinetic model with a quantitative systems pharmacology and toxicology (PBPK-QSP-TOX) model for statins in patients with normal kidney function and in different stages of chronic kidney disease (CKD). The QSP model was informed by 2753 measurements of circulating LDL concentrations in 1147 patients (NCT00654537). The TOX model was informed by a meta-analysis of creatine kinase elevation incidence per statin dose in 30 clinical studies (49,284 patients). The CKD populations accounted for disease related changes to 1) anatomy and physiology, 2) drug enzymes and transporters expression and 3) lipoprotein metabolism. This study provides a qualified PBPK-QSP-TOX model for statins that accurately describe plasma concentration-time profiles, lipid-lowering effect and myotoxicity risk over investigated dose range for patients with normal kidney function and varying degree of CKD.