title: Comparative bioavailability and tolerability of a single 20-mg dose of two fluoxetine hydrochloride dispersible tablet formulations in fasting, healthy Chinese male volunteers: an open-label, randomized-sequence, two-period crossover study.
abstract: BACKGROUND
  The proprietary formulation of fluoxetine hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. Pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed to market generic fluoxetine in China.
  
  
  OBJECTIVE
  The aim of this study was to compare the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of fluoxetine hydrochloride 20 mg in a fasting, healthy Chinese male population.
  
  
  METHODS
  This 10-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test or reference formulation, followed by a 35-day washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties (including C(max), T(max), AUC(0-t), AUC(0-∞), and t(½)), blood samples were obtained over a 672-hour period after dosing. Plasma concentrations of fluoxetine and its active metabolite, norfluoxetine, were analyzed using a validated LC-MS/MS method. The formulations were to be considered bioequivalent if the ln-transformed ratios (test/ reference) of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125%, as established by the US Food and Drug Administration, and if the P values were <0.05 for the 90% CIs. Signs and symptoms of adverse effects of fluoxetine hydrochloride such as nausea, vomiting, insomnia, somnolence, anxiety, and nervousness, as well as any untoward effects, were collected using a daily written questionnaire and recorded by the study physicians. Tolerability was assessed using monitoring of vital signs, physical ex- amination, ECG, and routine blood and urine tests, along with blood biochemical tests, at the start as well as at the end of the study.
  
  
  RESULTS
  Twenty-four subjects were enrolled and completed the study (mean [SD] age, 24.4 [2.3] years [range, 20-30 years]; weight, 63.6 [8.5] kg [range, 51.2-86.8 kg]; height, 1.72 [0.07] m [range, 1.57-1.91 m]). The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of 2 different populations (poor and extensive metabolizers). Data from the one poor metabolizer were excluded from the pharmacokinetics data summarized. In extensive metabolizers, the mean (SD) C(max) for fluoxetine with the test formulation was 11.786 (3.459) ng/mL and T(max) was 5.48 (2.06) hours. With the reference formulation, the corresponding values were 11.754 (3.292) ng/mL and 6.26 (5.77) hours, respectively. The t(½) values with the test and reference formulations were 30.86 (7.61) and 30.96 (6.91) hours, respectively. For norfluoxetine, mean C(max) with the test formulation was 14.177 (4.957) ng/mL and T(max) was 58.48 (31.67) hours; the corresponding values for the reference formulation were 13.828 (4.838) ng/mL and 57.91 (25.75) hours. The t(½) values with the test and reference formulations were 130.91 (42.04) and 128.79 (52.72) hours, respectively. For fluoxetine, the 90% CIs (in extensive metabolizers only) for the In-transformed C(max), AUC(0-168), and AUC(0-∞) were 92.0% to 108.4%, 95.7% to 110.3%, and 97.4% to 111.3%, respectively (all, P < 0.001). For norfluoxetine, the 90% CIs for the ln-transformed C(max), AUC(0-672), and AUC(0-∞) were 93.7% to 110.7%, 98.9% to 111.4%, and 98.8% to 110.9% (all, P < 0.001). No period or sequence effects were observed for any pharmacokinetic variable in the extensive metabolizers. No adverse events were reported by the volunteers or found with results of clinical laboratory testing.
  
  
  CONCLUSIONS
  This single-dose study found that the test and reference formulations of fluoxetine hydro- chloride met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated.
authors.affiliation: Clinical Trial Organization for Pharmaceutical Products of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Shi
authors.forename: Yani
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wu
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.forename: Fandian
authors.initials: F
authors.lastname: Zeng
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002681:China; D002853:Chromatography, Liquid / Q000379:methods; D018592:Cross-Over Studies; D016568:Drugs, Generic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005215:Fasting; D005473:Fluoxetine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008297:Male; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013607:Tablets; D053719:Tandem Mass Spectrometry / Q000379:methods; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D016568:Drugs, Generic; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; D013607:Tablets; C036139:norfluoxetine