4β-Hydroxycholesterol level significantly correlates with steady-state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients

Abstract

Aim: 4β-Hydroxycholesterol (4βOHC) is sensitive towards induction or inhibition of CYP3A4, but its potential usefulness as a dosing biomarker remains to be demonstrated. The aim of this study was to investigate the correlation between 4βOHC levels and steady-state concentrations (Css) of quetiapine, a CYP3A4 substrate with high presystemic metabolism, in psychiatric patients.

Methods: Serum samples from 151 patients treated with quetiapine as immediate release (IR; n = 98) or slow release (XR; n = 53) tablets were included for analysis of 4βOHC. In all patients, Css of quetiapine had been measured at trough level, i.e. 10-14 and 17-25 h post-dosing for IR and XR tablets, respectively. Correlations between 4βOHC levels and dose-adjusted Css (C/D ratios) of quetiapine were tested by univariate (Spearman's) and multivariate (multiple linear regression) analyses. Gender, age (≥60 vs. <60 years) and tablet formulation were included as potential covariates in the multivariate analysis.

Results: Correlations between 4βOHC levels and quetiapine C/D ratios were highly significant both for IR- and XR-treated patients (P < 0.0001). Estimated Spearman r values were -0.47 (95% confidence interval -0.62, -0.30) and -0.56 (-0.72, -0.33), respectively. The relationship between 4βOHC level and quetiapine C/D ratio was also significant in the multiple linear regression analysis (P < 0.001), including gender (P = 0.023) and age (P = 0.003) as significant covariates.

Conclusions: The present study shows that 4βOHC level is significantly correlated with steady-state concentration of quetiapine. This supports the potential usefulness of 4βOHC as a phenotype biomarker for individualized dosing of quetiapine and other drugs where systemic exposure is mainly determined by CYP3A4 metabolism.

Keywords: 4β-hydroxycholesterol; CYP3A4; biomarker; quetiapine.

Figure 1

Relationship between unadjusted 4β‐hydroxycholesterol levels (4βOHC, nmol l⁻¹) and 4βOHC‐to‐cholesterol (C) ratios (4βOHC/C) in the 86 patients where residual sample volumes were sufficient for reanalysis of both 4βOHC and C. P‐value estimated by Spearman's rank correlation test (r [rho] = correlation coefficient)

Figure 2

Correlations between 4β‐hydroxycholesterol (4βOHC) levels and (i) dose‐adjusted serum concentration (C/D ratio) of quetiapine (Q) (left panel), and (ii) N‐desalkylquetiapine‐to‐quetiapine (NDQ/Q) metabolic ratios (right panel), for immediate release (IR), extended release (XR) and pooled samples (IR + XR). P‐values estimated by Spearman's rank correlation tests (r [rho] = correlation coefficient)