Clinical Pharmacokinetics

, Volume 46, Issue 10, pp 885–895

Lack of Bioequivalence between Different Formulations of Isosorbide Dinitrate and Hydralazine and the Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine

The V-HeFT Paradox
  • S. William Tam
  • Michael L. Sabolinski
  • Manuel Worcel
  • Milton Packer
  • Jay N. Cohn
Original Research Article

DOI: 10.2165/00003088-200746100-00006

Cite this article as:
Tam, S.W., Sabolinski, M.L., Worcel, M. et al. Clin Pharmacokinet (2007) 46: 885. doi:10.2165/00003088-200746100-00006

Abstract

Objective

To investigate whether the apparent discrepancy between the efficacy of the combination of isosorbide dinitrate (ISDN) and hydralazine demonstrated in the first V-HeFT trial (V-HeFT I) and that in V-HeFT II could be explained by pharmacokinetic differences in the study drug formulations, and to compare the pharmacokinetic profile of the fixed-dose combination of ISDN/hydralazine (FDC ISDN/HYD; BiDil®) formulation used in A-HeFT with that of the V-HeFT study drug formulations.

Study participants and methods

A bioequivalence study was performed (n = 18–19 per group) comparing the ISDN and hydralazine formulations used in V-HeFT I, V-HeFT II and A-HeFT in healthy volunteer men and women aged 18–40 years. In phase A of the study, subjects received a reference solution of hydralazine hydrochloride/ISDN (37.5mg/10mg) orally. Slow acetylators were identified and randomised into three groups in phase B to receive a single oral dose of identical amounts of hydralazine hydrochloride/ISDN (37.5mg/10mg) from either (i) a hydralazine capsule plus an ISDN tablet (the V-HeFT I formulation); (ii) a hydralazine tablet plus an ISDN tablet (the V-HeFT II formulation); or (iii) FDC ISDN/HYD (the A-HeFT formulation). Blood/plasma concentrations of hydralazine and ISDN were determined from the blood samples taken between 0 and 36 hours.

Results

In phase B, the maximum observed concentrations (Cmax) were 65.9 ± 53.9, 28.2 ± 15.8 and 51.5 ± 54.3 ng/mL of unchanged hydralazine, and 23.1 ± 12.3, 21.7 ± 13.4 and 26.7 ± 18.7 ng/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. The area under the blood/plasma concentration-time curve (AUC) values were 32.6 ± 13.4, 23.3 ± 15.1 and 32.6 ± 18.5 ng · h/mL of hydralazine, and 24.4 ± 9.0, 24.8 ± 8.0 and 23.5 ± 6.3 ng · h/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. For comparison of bioequivalence, the Cmax and AUC were normalised to 65kg bodyweight, and point estimates and 90% confidence intervals of the Cmax ratios, AUC ratios and ratios of the AUC in phase B normalised for clearance by the AUC in phase A (AUCR) were calculated. The three formulations were not bioequivalent based on the Cmax and AUC comparisons.

Conclusions

The blood concentrations of hydralazine obtained with the tablet formulation tested in V-HeFT II were markedly lower than those obtained with the capsule formulation tested in V-HeFT I or the FDC ISDN/HYD single tablet used in A-HeFT. The apparently modest effect on survival observed in V-HeFT II could be explained in part by the poor hydralazine bioavailability of the tablet preparation used in this trial. ISDN exposures were similar in the two trials. The ISDN-hydralazine formulation used in V-HeFT II was not bioequivalent to the formulation used in V-HeFT I or to the FDC ISDN/HYD that had demonstrated a significant survival benefit in A-HeFT.

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • S. William Tam
    • 1
  • Michael L. Sabolinski
    • 1
  • Manuel Worcel
    • 1
  • Milton Packer
    • 2
  • Jay N. Cohn
    • 3
  1. 1.NitroMed, Inc.LexingtonUSA
  2. 2.University of Texas Southwestern Medical CenterDallasUSA
  3. 3.University of MinnesotaMinneapolisUSA