Tam S William, Sabolinski Michael L, Worcel Manuel, Packer Milton, Cohn Jay N
NitroMed, Inc., Lexington, Massachusetts 02421, USA.
Clin Pharmacokinet. 2007;46(10):885-95. doi: 10.2165/00003088-200746100-00006.
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.
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 (C(max)) 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 x h/mL of hydralazine, and 24.4 +/- 9.0, 24.8 +/- 8.0 and 23.5 +/- 6.3 ng x h/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. For comparison of bioequivalence, the C(max) and AUC were normalised to 65kg bodyweight, and point estimates and 90% confidence intervals of the C(max) 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 C(max) 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.
研究在首个退伍军人高血压治疗研究（V-HeFT I）中所证实的硝酸异山梨酯（ISDN）与肼苯哒嗪联合用药疗效和V-HeFT II中的疗效之间明显差异，是否可由研究药物制剂的药代动力学差异来解释，并比较A-HeFT中使用的ISDN/肼苯哒嗪固定剂量复方制剂（FDC ISDN/HYD；BiDil）与V-HeFT研究药物制剂的药代动力学特征。
进行了一项生物等效性研究（每组n = 18 - 19），比较V-HeFT I、V-HeFT II和A-HeFT中使用的ISDN和肼苯哒嗪制剂在18 - 40岁健康志愿者男性和女性中的情况。在研究的A阶段，受试者口服盐酸肼苯哒嗪/ISDN（37.5mg/10mg）的参比溶液。确定慢乙酰化者，并在B阶段随机分为三组，接受单剂量口服相同量的盐酸肼苯哒嗪/ISDN（37.5mg/10mg），分别来自：（i）肼苯哒嗪胶囊加ISDN片（V-HeFT I制剂）；（ii）肼苯哒嗪片加ISDN片（V-HeFT II制剂）；或（iii）FDC ISDN/HYD（A-HeFT制剂）。在0至36小时采集的血样中测定肼苯哒嗪和ISDN的血/血浆浓度。
在B阶段，V-HeFT I、V-HeFT II和A-HeFT制剂中，未变化的肼苯哒嗪的最大观察浓度（C(max)）分别为65.9±53.9、28.2±15.8和51.5±54.3 ng/mL，ISDN分别为23.1±12.3、21.7±13.4和26.7±18.7 ng/mL。血/血浆浓度-时间曲线下面积（AUC）值，V-HeFT I、V-HeFT II和A-HeFT制剂中，肼苯哒嗪分别为32.6±13.4、23.3±15.1和32.6±18.5 ng·h/mL，ISDN分别为24.4±9.0、24.8±8.0和23.5±6.3 ng·h/mL。为比较生物等效性，将C(max)和AUC按65kg体重进行标准化，并计算C(max)比值、AUC比值以及B阶段经A阶段AUC标准化清除率后的AUC比值（AUCR）的点估计值和90%置信区间。基于C(max)和AUC比较，这三种制剂并非生物等效。
V-HeFT II中测试的片剂制剂所获得的肼苯哒嗪血药浓度明显低于V-HeFT I中测试的胶囊制剂或A-HeFT中使用的FDC ISDN/HYD单片制剂。V-HeFT II中观察到的对生存的明显适度影响，部分可由该试验中使用的片剂制剂的肼苯哒嗪生物利用度差来解释。两次试验中ISDN的暴露情况相似。V-HeFT II中使用的ISDN-肼苯哒嗪制剂与V-HeFT I中使用的制剂或在A-HeFT中已证明具有显著生存获益的FDC ISDN/HYD制剂并非生物等效。
