Validation of a novel direct method to determine reduced adherence to atorvastatin therapy
Authors: Munkhaugen J M , Kristiansen O K , Pivoriunas J P , Fagerland M W F , Bergan S B , Sverre E S , Husebye E H , Vethe N T V 
Published: May 2023

Abstract

Funding Acknowledgements
Type of funding sources: Public hospital(s). Main funding source(s): Drammen hospital.

Introduction
Objective methods to monitor statin adherence may be a useful supplement to improve lipid management. We have recently established a test procedure with cut-off values that discriminate reduced adherence to atorvastatin therapy, defined by ≥2 doses omitted, by liquid chromatography–tandem mass spectrometry measurements of plasma drug concentrations.

Purpose
To validate our direct method for atorvastatin adherence in a larger sample, and to optimize previous cut-off values of reduced adherence according to pharmacokinetic variability.

Methods
We designed a clinical pharmacokinetic adherence study with 59 participants treated with atorvastatin 20 mg (N=20), 40 mg (N=20) and 80 mg (N=19). All were instructed to administer atorvastatin between 7 and 9 AM for at least seven days prior to study start to ensure steady-state drug concentrations. At the first study day, they met at the hospital outpatient clinic without having taken their morning dose. Two blood samples were collected with a one-hour interval (t24h and t25h) to detect any unscheduled morning dose. The participants temporarily stopped dosing and returned to the outpatient clinic the subsequent four days for blood samples for analyses of drug concentrations. Dose-normalized levels of atorvastatin plus all five major metabolites off statin treatment (t72h) were validated against the previously derived cut-off by calculating diagnostic sensitivity and specificity. Optimization of the cut-off value was sought by comparing dose-normalized concentrations off statin (t72h) with the adherence state at baseline (t24h).

Results
Mean age was 65.5 (SD 11.1) years, 31% women and 42% had atherosclerotic CVD. No participants had a significant increase in drug levels at baseline, confirming no ingestion of an unscheduled morning dose. The sum of parent drug and all major metabolites correlated moderately with the dose taken (Spearman’s rho= 0.40, 95% CI 0.15-0.60) at baseline (t24h). Hypo- or hyperthyroidism (β from linear regression 0.42, 95% CI 0.17–0.66) and diabetes (β 0.30, 95% CI 0.04–0.34) were associated with dose-normalized trough concentrations of atorvastatin plus metabolites in adjusted analyses, whereas age, gender, body weight, liver function or total number of drugs were not. Our previously suggested cut-off for reduced adherence (≥2 doses omitted), i.e. dose-normalized sum of atorvastatin plus metabolites &lt;0.10 nM/mg, provided a sensitivity of 97% and a specificity of 95%. An alternative cut-off at &lt;0.065 nM/mg provided a sensitivity of 90% and a specificity of 100%. With this alternative cut-off, no adherent participants would be misclassified with reduced adherence.

Conclusion
This validation study confirms that our direct method discriminate adherence from reduced adherence to atorvastatin therapy with high diagnostic accuracy. The method may be advantageous for the improvement of lipid management in clinical practice and serve as a useful tool in future studies.