Model-Based Approaches to Characterize Clinical Pharmacokinetics of Atorvastatin and Rosuvastatin in Disease State

Abstract

Cardiovascular disorders are the leading cause of death in the United States. Members of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) class of lipid-lowering drugs are used worldwide for the prevention and treatment of cardiovascular disorders. Cardiovascular disorders are the primary cause of morbidity and mortality in patients with diabetes mellitus and obesity as well as renal and liver transplantation. The rising global burden of these chronic disorders has resulted in long-term use of statins to prevent and treat cardiovascular disorders in diverse patient populations. Several statins are commercially available; however, atorvastatin calcium (Lipitor®, Pfizer Pharmaceuticals, NY) is the world’s top selling medication of all time; whereas, rosuvastatin calcium (Crestor®, AstraZeneca, DE) is the most efficacious member of statin family. Although, statins are well-tolerated, approximately 7% of patients on statin therapy experience myotoxicity, which is ranging from a mild condition called myalgia to a rare but potentially fatal rhabdomyolysis requiring hospitalization. A meta analysis study reported by the United States FDA indicated three times higher incidence of rhabdomyolysis in patients with diabetes mellitus. Previously published in vitro and clinical studies identified the role of lactone metabolites in myopathy. Our group found significantly elevated plasma concentrations of atorvastatin lactone metabolites in the stable kidney transplant recipients with diabetes mellitus. Our study indicated that reduced clearance of lactone could be attributed to decreased activity of cytochrome P450 (CYP) 3A4, which is the main drug metabolizing enzyme. Prior studies assessed the effect of genetic polymorphism in drug metabolizing enzymes and transporters on pharmacokinetics and toxicological properties of parent drug and lactone metabolite in healthy Finish and Korean populations. Currently, limited information is available on the effect of concurrent diseases and genetic polymorphisms of drug metabolizing enzymes and transporters on pharmacokinetics of acid and lactone forms of atorvastatin. Altered pharmacokinetics of atorvastatin acid or lactone in concomitant diseases possibly influences the clinical outcome, resulting in unfavorable benefit/risk ratio. In this study, we have assessed the impact of inherent demographic characteristics in conjunction with coexisting diseases and genetic polymorphisms using a population pharmacokinetic analysis utilizing a nonlinear mixed effect model to identify potential covariates that explain the variability in pharmacokinetic properties of acid and lactone forms of atorvastatin. A physiologically-based pharmacokinetic modeling approach was used for the prediction of pharmacokinetics of orally administered atorvastatin acid and rosuvastatin acid along with their major metabolites from in vitro data allowing mechanistic characterization of the observed concentration-time profile. A