ABSTRACT
OBJECTIVE: The purpose of this study was to assess bioequivalence between a generic and a brand quetiapine 400 mg prolonged-release (PR) formulation (Pharmathen S.A.; AstraZeneca Seroquel Prolong®<) in healthy volunteers under steady-state conditions. METHODS: Randomized, open-label, steady-state, 2-way crossover design in 48 subjects under fasting conditions. As a quetiapine dose of 400 mg was suspected to be high when administered to healthy subjects, we proceeded with an innovative design where subjects were titrated up using 150 mg, 200 mg, and 300 mg daily doses; first treatment (days 4 - 9) and second treatment (days 10 - 15), and then a tapering down phase (days 16 - 17). Blood samples were collected in EDTA K2< tubes prior to each dosing and over a 24-hour sampling schedule on days 9 and 15. Quetiapine was measured in plasma using LC-MS/MS assay (range 2.5 - 2,000 ng/mL). Pharmacokinetic analyses were performed using non-compartmental method to evaluate AUC>τ, Cmax, and Cmin. ANOVA was performed on the ln-transformed data and 90% confidence interval (90% CI) was determined. Bioequivalence was concluded if the 90% CI of AUCτ, Cmin, and Cmax fell within 80.00 - 125.00%. RESULTS: 46 volunteers completed the study and were included in the analyses. Arithmetic mean (SD) for AUCτ were 7,161.18 (3,687.10) ng×h/mL and 7,184.27 (3,304.29) ng×h/mL, Cmax were 595.61 (345.98) ng/mL and 597.06 (253.67) ng/mL, and Cmin were 119.47 (84.24) ng/mL and 124.22 (137.68) ng/mL, respectively, for the test and reference. All pharmacokinetic parameters met the acceptance criteria as the 90% CI felt within 95.98 - 104.21%, 91.48 - 105.89%, and 86.32 - 104.49% for AUCτ, Cmax, and Cmin, respectively. Both formulations were well tolerated and no serious adverse events were reported. CONCLUSION: Our innovative design allowed safe administration of quetiapine 400 mg PR daily doses to healthy volunteers. Both Pharmathen and AstraZeneca formulations were well tolerated and bioequivalent under steady-state conditions.â©.
