Investigating the clinical factors and comedications associated with circulating levels of atorvastatin and its major metabolites in secondary prevention.

Richard M. Turner,Vanessa Fontana,Richard FitzGerald,Munir Pirmohamed,Andrew P. Morris

doi:10.1111/bcp.14133

Richard M. Turner, Vanessa Fontana + Show 3 more

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https://doi.org/10.1111/bcp.14133

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Abstract

AimsThe lipid‐lowering drug, atorvastatin (ATV), is 1 of the most commonly prescribed medications worldwide. The aim of this study was to comprehensively investigate and characterise the clinical factors and comedications associated with circulating levels of ATV and its metabolites in secondary prevention clinical practice.MethodsThe plasma concentrations of ATV, 2‐hydroxy (2‐OH) ATV, ATV lactone (ATV L) and 2‐OH ATV L were determined in patients 1 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.ResultsA total of 571 patients were included; 534 and 37 were taking ATV 80 mg and 40 mg daily, respectively. Clinical factors associated with ATV and/or its metabolite levels included age, sex, body mass index and CYP3A inhibiting comedications. Smoking was newly associated with increased ATV lactonisation 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 = .0071 for 2‐OH ATV L) was observed. Overall model R2 values were 0.14–0.24.ConclusionMultiple 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.

Highlights

Statins are amongst the most highly prescribed medications worldwide
The main findings of this study were: confirmation of the impact of several clinical factors on exposure to ATV, novel extension of these associations to other ATV metabolites and/or analyte ratios, and identification of new factors associated with ATV analyte exposures including smoking, pump inhibitors (PPIs), and loop diuretics with the latter attributable principally to furosemide
Lansoprazole and omeprazole are substrates and inhibitors of CYP2C19 and cytochrome P450 3A4 (CYP3A4),22,23,46,47 CYP3A4-mediated inhibition would not account for the uniform increase in all ATV analytes observed here; possible explanations include an increase in ATV bioavailability secondary to a PPI-induced rise in gastric pH, or inhibition of an elimination transporter

Summary

| INTRODUCTION

Statins are amongst the most highly prescribed medications worldwide. Atorvastatin (ATV) is currently the guideline-recommended first-line hypolipidaemic drug for primary and secondary prevention of cardiovascular (CV) disease (CVD). All statins, including ATV, can result in SAM, which ranges from common myalgias (in ~5% patients9) where causal attribution may be difficult, through to myopathies of increasing severity with elevated plasma creatine kinase levels (~0.1% patients) to rare rhabdomyolysis (0.1–8.4/100 000 patient-years).[3] the mechanisms remain incompletely understood, factors that increase systemic statin exposure appear to increase the risk of SAM These factors include higher statin dose, advanced age, low body mass index (BMI), and comedications that inhibit CYP3A4 in patients on a statin that is a CYP3A4 substrate (ATV, simvastatin lovastatin).[3,10,11] Statin lactones are considered more myotoxic than statin acids.[12]. To the best of knowledge, a real-world assessment of ATV levels on this scale has not been previously reported

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