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