Investigating the clinical factors and co-medications associated with circulating levels of atorvastatin and its major metabolites in secondary prevention.
The lipid-lowering drug, atorvastatin (ATV), is one of the most commonly prescribed medications worldwide. The aim of this study was to comprehensively investigate and characterise the clinical factors and co-medications associated with circulating levels of ATV and its metabolites in secondary prevention clinical practice. The plasma concentrations of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L) and 2-OH ATV L were determined in patients one month after hospitalisation for a non-ST elevation acute coronary syndrome. Factors were identified using all subsets multivariable regression and model averaging with the Bayesian information criterion. Exploratory genotype-stratified analyses were conducted using ABCG2 rs2231142 (Q141K) and CYP2C19 metaboliser status to further investigate novel associations. A total of 571 patients were included; 534 and 37 were taking ATV 80mg and 40mg daily, respectively. Clinical factors associated with ATV and/or its metabolite levels included age, sex, body mass index, and CYP3A inhibiting co-medications. Smoking was newly associated with increased ATV lactonization and reduced hydroxylation. Proton pump inhibitors (PPIs) and loop diuretics were newly associated with modestly increased levels of ATV (14% and 38%, respectively) and its metabolites. An interaction between PPIs and CYP2C19 metaboliser status on exposure to specific ATV analytes (e.g. interaction p=0.0071 for 2-OH ATV L) was observed. Overall model R2 values were 0.14-0.24. Multiple factors were associated with circulating ATV and metabolite levels, including novel associations with smoking and drug-drug(-gene) interactions involving PPIs and loop diuretics. Further investigations are needed to identify additional factors that influence ATV exposure.
PubMed Abstracts
PubMed Abstracts