title: Comparison of scaled-average, population, and individual bioequivalence on 2 tablets of pitavastatin calcium: a 3-period, reference-replicated, crossover study in healthy Chinese volunteers.
abstract: BACKGROUND
  Pitavastatin, a fully synthetic β-hydroxy-β-methylglutaryl-coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject variability and interchangeability of this newly developed generic product and the branded innovator product have rarely been investigated in the Chinese population.
  
  
  OBJECTIVE
  The aim of this study is to develop and compare the scaled-average, population, and individual bioequivalence (BE) of pitavastatin calcium tablets in healthy Chinese volunteers. This study will be used to allow for the interchangeability (switchability and prescribability) of the 2 products in clinical medication in China.
  
  
  METHODS
  A single-dose, reference-replicated, 3-period crossover BE study was conducted in 36 healthy male volunteers. Plasma samples were collected before and after oral administration of 2-mg test or reference tablets. A LC-MS/MS method was used to determine the concentration of pitavastatin calcium. A noncompartmental method was used to investigate the pharmacokinetic parameters. The ANOVA and 90% CIs of ln(AUC0-t) and ln(Cmax) were used for statistical analysis of scaled-average BE. A nonparametric test (Wilcoxon signed rank test) was performed to Tmax. The analyses of population BE and individual BE were used to assess the switchability and prescribability of the 2 products.
  
  
  RESULTS
  Thirty-six volunteers were enrolled in this clinical research; 33 volunteers completed the 3 treatment periods. The mean (SD) relative bioavailability calculated from the ratios (T/R) of AUC0-t was 101.3% (19.7%). The mean ln(AUC0-t) and ln(Cmax) were 98.64 (90% CI, 93.44-104.13) and 98.68 (90% CI, 91.88-105.99) within previously stipulated ranges recommended by the US Food and Drug Administration and the China Food and Drug Administration (CFDA). The intrasubject %CVs of AUC0-t and Cmax were 12.0% and 18.0% for the reference tablet and 13.0% and 17.0% for the test tablet. No significant differences were found among Tmax (0.742 ± 0.276, 0.674 ± 0.202, and 0.689 ± 0.226, respectively) for reference tablet 1, reference Supplemental Table II in the online version at 10.1016/j.clinthera.2014.06.21, and test tablet by a Wilcoxon test (P > 0.05). For ln(AUC0-t) and ln(Cmax), the statistical test-reference ratios were 99.13% and 98.95%, respectively. After inspecting the results for reference and mixed scaling, all the upper confidence limits were <0; therefore, population and individual BE were given.
  
  
  CONCLUSIONS
  In the healthy Chinese males, the generic and branded name tablets of pitavastatin calcium are bioequivalent at the rate and extent of absorption after a comparison of scaled-average, population, and individual BE and thus may be used interchangeably. Both the formulations are generally well tolerated. Chinese Clinical Trial identifier: ChiCTR-TTRCC-13003973.
authors.affiliation: GCP Center, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Huang
authors.affiliation: GCP Center, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Zi-Qiang
authors.initials: ZQ
authors.lastname: Li
authors.affiliation: Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Gui-Xiang
authors.initials: GX
authors.lastname: Pan
authors.affiliation: GCP Center, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Li
authors.affiliation: GCP Center, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: GCP Center, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Jin-Xia
authors.initials: JX
authors.lastname: Sun
authors.affiliation: GCP Center, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Xu-Fang
authors.initials: XF
authors.lastname: Gu
authors.affiliation: GCP Center, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China. Electronic address: wbh3432@sina.com.
authors.forename: Bao-He
authors.initials: BH
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D001682:Biological Availability; D002681:China; D018592:Cross-Over Studies; D057915:Drug Substitution; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D016568:Drugs, Generic; D004791:Enzyme Inhibitors; D011804:Quinolines; D013607:Tablets; C108475:pitavastatin
keywords: individual bioequivalence; pitavastatin calcium; population bioequivalence (PBE); reference-replicated; scaled-average bioequivalence