Clinical Pharmacokinetics

, Volume 46, Issue 10, pp 885–895 | Cite as

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



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.


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.


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.



This study was sponsored by NitroMed, Inc. S. William Tam and Manuel Worcel are employees of NitroMed and hold stock and stock options in NitroMed. Michael L. Sabolinski is a former employee of NitroMed and holds stock options in NitroMed. Milton Packer is a consultant to NitroMed. Jay N. Cohn is a consultant to NitroMed and has royalty arrangements with NitroMed related to sales of BiDil®. The authors have no other conflicts of interest to declare that are directly relevant to the content of this study.

The authors would like to thank Virginia Braman of NitroMed for assistance in the preparation of this manuscript.


  1. 1.
    Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration cooperative study. N Engl J Med 1986; 314: 1547–52PubMedCrossRefGoogle Scholar
  2. 2.
    Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–10PubMedCrossRefGoogle Scholar
  3. 3.
    The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302CrossRefGoogle Scholar
  4. 4.
    The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685–91CrossRefGoogle Scholar
  5. 5.
    Jong P, Yusuf S, Rousseau MF, et al. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet 2003; 361: 1843–8PubMedCrossRefGoogle Scholar
  6. 6.
    Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999; 100: 2312–8PubMedCrossRefGoogle Scholar
  7. 7.
    Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in Blacks with heart failure. N Engl J Med 2004; 351: 2049–57PubMedCrossRefGoogle Scholar
  8. 8.
    Data on file, NitroMed, Inc., 1999Google Scholar
  9. 9.
    Center for Drug Evaluation and Research, US FDA. Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products — general considerations. Revision 1 [online]. Rockville (MD): Center for Drug Evaluation and Research, 2003 Mar. Available from URL: [Accessed 2007 Sep 5]Google Scholar
  10. 10.
    Relling MV. Polymorphic drug metabolism. Clin Pharm 1989; 8: 852–63PubMedGoogle Scholar
  11. 11.
    Ludden TM. Nonlinear pharmacokinetics: clinical implications. Clin Pharmacokinet 1991; 20: 429–46PubMedCrossRefGoogle Scholar
  12. 12.
    Reidenberg MM, Drayer D, de Marco AL, et al. Hydralazine elimination in man. Clin Pharmacol Ther 1973; 14: 970–7PubMedGoogle Scholar
  13. 13.
    Shepherd AMM, Irving NA, Ludden TM, et al. Effect of oral dose size on hydralazine kinetics and vasodepressor response. Clin Pharmacol Ther 1984; 36: 595–600PubMedCrossRefGoogle Scholar
  14. 14.
    Crawford MH, Ludden TM, Kennedy GT. Determinants of systemic availability of oral hydralazine in heart failure. Clin Pharmacol Ther 1985; 38: 538–43PubMedCrossRefGoogle Scholar
  15. 15.
    Ludden TM, Rotenberg KS, Ludden LK, et al. Relative bioavailability of immediate and sustained-release of hydralazine formulations. J Pharm Sci 1988; 7: 1026–32CrossRefGoogle Scholar
  16. 16.
    Fung HL, McNiff EF, Ruggirello D, et al. Kinetics of isosorbide dinitrate and relationships to pharmacological effects. Br J Clin Pharmacol 1981; 11: 579–90PubMedCrossRefGoogle Scholar
  17. 17.
    Franciosa JA, Weber KT, Levine TB, et al. Hydralazine in the long-term treatment of chronic heart failure: lack of difference from placebo. Am Heart J 1982; 104: 587–94PubMedCrossRefGoogle Scholar
  18. 18.
    Mulrow CD, Mulrow JP, Linn WD, et al. Relative efficacy of vasodilator therapy in chronic congestive heart failure: implications of randomized trials. JAMA 1988; 259: 3422–6PubMedCrossRefGoogle Scholar
  19. 19.
    Kanamasa K, Hayashi T, Takenaka T, et al. Continuous longterm dosing with oral slow-release isosorbide dinitrate does not reduce incidence of cardiac events in patients with healed myocardial infarction. Clin Cardiol 2001; 24: 608–14PubMedCrossRefGoogle Scholar
  20. 20.
    Kanamasa K, Hayashi T, Kimura A, et al. Long-term, continuous treatment with both oral and transdermal nitrates increase cardiac events in healed myocardial infarction patients. Angiology 2002; 53: 399–408PubMedCrossRefGoogle Scholar
  21. 21.
    Rauhala P, Chiueh CC. Effects of atypical antioxidative agents, S-nitrosoglutathione and manganese, on brain lipid peroxidation induced by iron leaking from tissue disruption. Annals N Y Acad Sci 2000; 899: 238–54CrossRefGoogle Scholar
  22. 22.
    Münzel T, Kurz J, Rajagopalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membranebound NADH oxidase: a new action for an old drug. J Clin Invest 1996; 98: 1465–70PubMedCrossRefGoogle Scholar
  23. 23.
    Hare JM. Nitroso-redox balance in the cardiovascular system. N Engl J Med 2004; 351: 2112–4PubMedCrossRefGoogle Scholar
  24. 24.
    Bauer JA, Fung HL. Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure. Circulation 1991; 84: 35–9PubMedCrossRefGoogle Scholar
  25. 25.
    Gogia H, Mehra A, Parikh S, et al. Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure. J Am Coll Cardiol 1995; 26: 1575–80PubMedCrossRefGoogle Scholar
  26. 26.
    Elkayam U. Prevention of nitrate tolerance with concomitant administration of hydralazine. Can J Cardiol 1996; 12 Suppl. C: 17C–21CPubMedGoogle Scholar

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

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