Despite extensive research on pharmacokinetic interactions between hydroxymethylglutaryl-CoA reductase inhibitors (statins) and fibrates, the underlying pharmacodynamic mechanisms contributing to the increased risk of rhabdomyolysis remain unclear. This study aimed to determine the differences among statins or fibrates in terms of their susceptibility to rhabdomyolysis. The data mining of FDA Adverse Event Reporting System (FAERS) suggested the association of both statins and fibrates with rhabdomyolysis and the add-on effect of their combinations. In rats, their administration was associated with outliers in creatine phosphokinase and myoglobin levels and a larger distribution of data than in the control. Additionally, co-administration of cerivastatin increased the gemfibrozil concentration in skin and muscle tissues by more than two-fold without an increase in systemic exposure to gemfibrozil, suggesting that an alteration in the pharmacokinetics of gemfibrozil might contribute to an increased risk of rhabdomyolysis when cerivastatin and gemfibrozil are co-administered. Taken together, caution is uniformly needed in combination therapy with statins and fibrates because of the increased risk of rhabdomyolysis.
Keywords: FAERS; cerivastatin; gemfibrozil; preclinical pharmacokinetics; rhabdomyolysis.
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