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

Summary

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-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 hours 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.

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