, Volume 53, Issue 5, pp 455-465
Date: 03 Jan 2014

Pharmacokinetics and Tolerability of Extended-Release Quetiapine Fumarate in Han Chinese Patients with Schizophrenia

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Abstract

Background and Objective

The extended-release formulation of quetiapine (quetiapine XR), which was developed to provide more convenient once-daily administration, has been widely studied to characterize its pharmacokinetics in Caucasian populations but has rarely been studied in an Asia population. This study was conducted to evaluate the pharmacokinetics and tolerability of quetiapine XR administered as a single dose (300 mg) and multiple doses (300, 600, and 800 mg) in Han Chinese patients with schizophrenia.

Methods

This was a single-center, open-label, single-dose and multiple-dose randomized study. Among the 55 randomized subjects, a total of 40 female or male patients in 300 mg (n = 13), 600 mg (n = 13), or 800 mg (n = 14) groups completed the study of quetiapine fumarate XR. The treatment phase consisted of 5 consecutive days and was preceded by a 1- to 2-day titration period for the 600 and 800 mg groups. Pharmacokinetic parameters for both quetiapine and N-desalkyl quetiapine (norquetiapine) were determined. The tolerability evaluation included adverse events (AEs) noted by monitoring, physical examinations, vital signs, and clinical laboratory tests.

Results

N-desalkyl quetiapine was formed from quetiapine with an approximate metabolite to parent ratio of 0.5 across the three dose groups. The geometric mean elimination half-life (t ½) of both quetiapine and N-desalkyl quetiapine was consistent for the three dosing groups (approximately 7 h for quetiapine and approximately 18 h for N-desalkyl quetiapine). The geometric mean maximum plasma concentrations (C max) at steady state (C max,ss) of quetiapine for the three groups were 467, 740, and 1,126 ng/mL, respectively, and for N-desalkyl quetiapine were 138, 262, and 426 ng/mL, respectively. The values for the geometric mean area under the plasma concentration–time curve over a dosing interval at the steady-state (AUCss) of quetiapine were 5,094, 7,685, and 13,237 ng·h/mL, respectively, and for N-desalkyl quetiapine were 2,284, 4,341, and 7,216 ng·h/mL, respectively. The apparent oral clearance (CL/F) of quetiapine at steady state appeared to be comparable across the three dose groups. The pharmacokinetics of quetiapine XR were dose-proportional across the dosage range employed. The most common AE was somnolence, but all of the reported AEs were mild. There were no serious AEs or other significant AEs.

Conclusion

Quetiapine fumarate XR has a dose-proportional pharmacokinetic profile at doses ranging from 300 to 800 mg once daily, and a slower time to reach C max and steady state after 3 days of sequential dosing. Therefore, it offers a simple and rapid dose-escalation option and more convenient once-daily administration. The three dosages of quetiapine fumarate XR were generally well-tolerated in this pharmacokinetic study of Han Chinese patients with schizophrenia.

Q. Li and Y. A. Su contributed equally to this work.