High Variability in Drug Pharmacokinetics Complicates Determination of Bioequivalence: Experience with Verapamil

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 AUC_0−t varied 3.8 fold among subjects and 5/9 subjects had >30% difference in AUC_0−t on the 2 days. After log transformation, the mean AUC_0−t ± %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 intra-subject 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 bioinequi valence.

Keywords: highly variable drugs; drug clearance; bioequivalence assessment; verapamil

Language: English

Document Type: Regular paper

Affiliations: 1: Apotex Inc., 150 Signet Dr., Weston, Ontario, Canada M9L 1T9. Faculty of Pharmacy, University of Toronto, Toronto, Ontario. 2: Apotex Inc., 150 Signet Dr., Weston, Ontario, Canada M9L 1T9. 3: Apotex Inc., 150 Signet Dr., Weston, Ontario, Canada M9L 1T9. Faculty of Pharmacy, University of Toronto, Toronto, Ontario. Division of Clinical Pharmacology, Hospital For Sick Children, Toronto, Ontario. To whom correspondence should be addressed