title: Pharmacokinetics and bioavailability comparison of generic and branded citalopram 20 mg tablets: an open-label, randomized-sequence, two-period crossover study in healthy Chinese CYP2C19 extensive metabolizers.
abstract: BACKGROUND
  Citalopram is a selective serotonin reuptake inhibitor (SSRI) mainly prescribed to treat major depression.
  
  
  OBJECTIVE
  The aim of this study was to compare the pharmacokinetic characteristics of a new and a branded citalopram 20 mg formulation to support the marketing authorization of the test formulation in China.
  
  
  METHODS
  A single-dose, open-label, randomized-sequence, two-period crossover design was used in this study. Healthy Chinese male cytochrome P450 (CYP) 2C19 extensive metabolizers, aged 18-40 years, were eligible to participate. CYP2C19 poor metabolizers were excluded, based on genotyping of genomic DNA from blood samples. Twenty-four subjects were randomly assigned to receive the test formulation followed by the reference formulation, and then vice versa. A 2-week washout occurred between study periods. Blood samples were collected for up to 144 h post-dose. Quantification was carried out using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated and analysed statistically. The two formulations were considered pharmacokinetically equivalent if the 90 % confidence intervals (CIs) of the log-transformed ratios (test/reference) of the maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC(last)), and area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were within the predetermined acceptance range (70-143 % for C(max); 80-125 % for AUC(last) and AUC(∞)) according to China State Food and Drug Administration bioequivalence guidelines. Tolerability was monitored by clinical assessment, vital signs, laboratory analysis and interviews with participants about adverse events.
  
  
  RESULTS
  A total of 24 participants, with a mean (SD) age of 26 (3) years (range 22-32 years), body weight of 65.2 (5.0) kg (range 53-73 kg), and height of 172.7 (4.9) cm (range 159-182 cm), were enrolled in this study. Both formulations showed similar pharmacokinetic profiles. Mean (SD) AUC(last), AUC(∞) and C(max) were 1436 (341) ng · h/mL, 1595 (381) ng · h/mL and 32.3 (5.9) ng/mL, respectively, for the test formulation, and 1444 (388) ng · h/mL, 1648 (504) ng · h/mL, 33.1 (7.4) ng/mL, respectively, for the reference formulation. Median (range) time to reach C(max) (t(max)) was 2 (1-12) hours (test) and 3 (1-6) hours (reference). The 90 % CIs of the treatment ratios for the ln-transformed values of C(max), AUC(last) and AUC(∞) were 92.5-103.6, 95.2-100.6 and 96.4-105.4, respectively. No significant difference was found between treatments with regard to pharmacokinetic parameters. Fifteen adverse events were reported during the study but none were considered serious.
  
  
  CONCLUSIONS
  This single-dose study found that the test and reference citalopram 20 mg tablets met the regulatory criteria for assuming bioequivalence in the selected healthy Chinese male subjects. Both formulations were well tolerated.
authors.affiliation: State Base of Clinical Trials, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Rong
authors.forename: Yiping
authors.initials: Y
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Yifan
authors.initials: Y
authors.lastname: Xie
authors.forename: Congying
authors.initials: C
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Shen
authors.forename: Huafang
authors.initials: H
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002681:China / Q000453:epidemiology; D002851:Chromatography, High Pressure Liquid; D015283:Citalopram / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010641:Phenotype; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D016568:Drugs, Generic; D017367:Selective Serotonin Reuptake Inhibitors; D013607:Tablets; C045793:CYP2C19 protein, human