Establishment and clinical application of a method for converting random quetiapine concentrations to steady-state...

To establish a pharmacokinetic model-based method for converting random concentrations of quetiapine (QTP) and its active metabolite N-desmethylquetiapine (N-QTP) to steady-state trough concentrations, and validate its component-specific accuracy using paired patient data to address the clinical challenge of interpreting non-standard time samples in therapeutic drug monitoring (TDM).

Core pharmacokinetic parameters (QTP half-life: 7 h; N-QTP half-life: 12 h) were confirmed via systematic literature review. Phase-specific conversion formulas were derived based on first-order kinetic decay, with 14 h post-dose as the standard trough time (midpoint of 12-16 h guideline window). A longitudinal validation cohort of 80 schizophrenia patients (steady-state QTP administration ≥7 days) was enrolled: each patient underwent two blood samplings on separate dosing days (1 random time point [2-26 h] and 1 standard 14 h trough sampling). Python was used to calculate conversion coefficients (1-48 h), and accuracy was validated by comparing QTP-specific, N-QTP-specific, and total estimated trough concentrations with concurrently measured trough concentrations (gold standard).

Conversion coefficients for 1-48 h were generated. Validation with paired data (n = 80) showed strong component-specific and overall agreement: For QTP alone, Pearson correlation coefficient (r) = 0.89 (P < 0.001), mean relative error (RE) = 10.1 % ± 4.2 % (range: 5.3 %-15.8 %), and 82.5 % of estimates with RE < 15 %; for N-QTP alone, r = 0.91 (P < 0.001), mean RE = 7.8 % ± 3.1 % (range: 3.2 %-13.2 %), and 93.8 % of estimates with RE < 15 %; for total concentration (QTP + N-QTP), r = 0.92 (P < 0.001), mean bias = -5.2 ng/mL (95 % CI: -11.7-1.3), limits of agreement (LOA) = -34.8-24.4 ng/mL, mean RE = 9.2 % ± 3.7 % (range: 4.8 %-14.5 %), and 87.5 % of estimates with RE < 15 %. Stratified analysis by sampling time point confirmed consistent accuracy across 2-26 h, with optimal performance at 6-10 h (RE < 9 %).

The conversion method, rigorously validated for both QTP and N-QTP with paired patient data, demonstrates robust component-specific and overall accuracy for clinical use. It provides a practical, eadily applicable lookup table to facilitate TDM interpretation when standard trough sampling is unfeasible, thereby supporting personalized quetiapine therapy for schizophrenia and bipolar disorder.