Plasma concentration of atorvastatin metabolites correlates with low-density lipoprotein cholesterol reduction in patients with coronary heart disease

Abstract

In this exploratory study from a randomized double-blinded crossover trial including 70 patients with coronary heart disease and self-perceived muscular side effects of statins, we aimed to determine the relationship between low-density lipoprotein cholesterol (LDL-C) reduction and atorvastatin metabolite plasma concentrations. All patients underwent a 7 weeks treatment period with atorvastatin 40 mg/day and a 7 weeks placebo period in random order. Nonlinear regression with a three-parameter equation explored the relationship between percentage LDL-C reduction (statin vs. placebo) and the pharmacokinetic variables. Mean LDL-C reduction was 49% (range 12% to 71%). The sum of 4-OH-atorvastatin acid and lactone correlated moderately with the LDL-C response (Spearman ρ 0.27, 95% confidence interval [CI]: 0.03 to 0.48). Accordingly, nonlinear regression showed R² of 0.14 (95% CI: 0.03 to 0.37, R² adjusted equaled 0.11). Even a perfect underlying correlation of 1.0 showed R² = 0.32 by simulation, using historical intra-individual LDL-C variation (8.5%). The 90% inhibitory concentration was 2.1 nmol/L, and the 4-OH-metabolite sum exceeded this threshold in 34% of the patients. In conclusion, trough plasma concentrations of 4-OH-atorvastatin metabolites correlated moderately to the LDL-C reduction. A plateau LDL-C response was observed above a pharmacokinetic threshold, below which the response was highly variable. The usefulness of monitoring concentrations of atorvastatin metabolites to optimize the individual dosage have limitations, but its supportive potential may be pursued in relevant patient subsets to achieve adequate efficacy at the lowest possible dose. The results add knowledge to the overall understanding of the variable LDL-C response mediated by atorvastatin.

Trial registration: ClinicalTrials.gov NCT03874156.

Keywords: LDL-cholesterol; adherence; atorvastatin; coronary heart disease; liquid chromatography-tandem mass spectrometry.

FIGURE 1

Percent wise change in low‐density lipoprotein cholesterol between placebo and atorvastatin 40 mg/day, sorted by the size of the reduction.

FIGURE 2

Patient concentrations of low‐density lipoprotein cholesterol (LDL‐C) while under placebo and atorvastatin 40 mg/day treatment (by order of treatment). One half (n = 35) of the patients in the intervention‐group had first seven‐week treatment with placebo and then seven‐week treatment with atorvastatin 40 mg/day. The other half first had treatment with atorvastatin and then placebo (n = 35). Mean LDL‐C was 4.2 (SD 1.0) mmol/L at the end of the placebo treatment period, and 2.1 (SD 0.6) mmol/L at the end of the atorvastatin 40 mg/day treatment period.

FIGURE 3

Plasma concentrations of atorvastatin (ATV) and its main metabolites 24 h after last dose. Lines represent median values. Data from intervention‐group (n =70). ATV, atrovastatin.

FIGURE 4

Percentage reduction in low ‐density lipoprotein cholesterol (LDL‐C) versus the hydroxylated atorvastatin acid and lactone metabolites concentration in blood plasma. The dotted lines represent 95% confidence interval for the likely location of the true curve (GraphPad).