Abstract:
PURPOSE:For the assessment of bioequivalence it is assumed that drug clearance in each subject on each of the study days is the same and any observed differences in AUC and/or Cmax between a brand and generic formulation are due to differences in bioavailability. We hypothesized that this assumption was invalid for highly variable drugs such as verapamil and tested it by comparing bioavailability for the brand vs itself. METHODS:To avoid any contribution from potential formulation differences, we evaluated bioavailability for isoptin SR 240 mg tablets in 9 healthy volunteers on 2 occasions separated by 1 week as part of a larger study. A validated HPLC assay was used to measure serial blood samples over 36 hours. RESULTS:The AUC0-1 varied 3.8 fold among subjects and 5/9 subjects had > 30% difference in AUC0-1 on the 2 days. After log transformation, the mean AUC0-1 +/- %cv (ng.h/mL) on Occasion 1 (878 +/- 38) was 23% greater (p = 0.031) than on Occasion 2 (713 +/- 41). The 90% confidence interval of Occasion 1/Occasion 2 was 106-143%. The Cmax varied > 9 fold (30-278 ng/mL) among subjects. The intrasubject difference between days ranged from -46% to +298%. The 90% confidence interval was 72-152% for Cmax. Since the same lot of Isoptin was used in the same subjects on 2 occasions, the observed differences must be due to biological variability in verapamil pharmacokinetics, not formulation differences. CONCLUSIONS:The intra-subject biological variability complicates bio-equivalence assessment and can lead to an erroneous assumption of bioinequivalence.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Tsang YC,Pop R,Gordon P,Hems J,Spino Mdoi
10.1023/a:1016040825844subject
Has Abstractpub_date
1996-06-01 00:00:00pages
846-50issue
6eissn
0724-8741issn
1573-904Xjournal_volume
13pub_type
临床试验,杂志文章abstract:PURPOSE:It was the aim of this study to synthesize and characterize a novel chitosan-glutathione (GSH) conjugate providing improved mucoadhesive and permeation-enhancing properties. METHODS:Mediated by carbodiimide and N-hydroxysuccinimide, glutathione was covalently attached to chitosan via the formation of an amide ...
journal_title:Pharmaceutical research
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更新日期:1997-04-01 00:00:00
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更新日期:1997-10-01 00:00:00
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更新日期:2018-05-22 00:00:00