Establishment and clinical application of a method for converting random quetiapine concentrations to steady-state trough concentrations.
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.
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.
Authors
Dong Dong, Qiu Qiu, Tan Tan, Zhu Zhu, Lv Lv, Chen Chen, Hu Hu, Ju Ju, Yin Yin
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