Mechanism of Action
The mechanism of action underlying the beneficial effects of BiDil in the treatment of heart failure has not been established.
Isosorbide dinitrate is a vasodilator affecting both arteries and veins. Its dilator properties result from the release of nitric oxide and the subsequent activation of guanylyl cyclase, and ultimate relaxation of vascular smooth muscle.
Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of chronically-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has response to nitrates been restored.
Hydralazine is a selective dilator of arterial smooth muscle. Animal data suggests that hydralazine may also mitigate tolerance to nitrates.
Absorption and Distribution
About 2/3 of a 50-mg dose of 14C-hydralazine HCl given in gelatin capsules was absorbed in hypertensive subjects. In patients with heart failure, mean absolute bioavailability of a single oral dose of hydralazine 75 mg varies from 10 to 26%, with the higher percentages in slow acetylators (See Metabolism and Elimination for Hydralazine). Administration of doses escalating from 75 mg to 1000 mg tid to congestive heart failure patients resulted in an up to 9-fold increase in the dose normalized AUC, indicating non-linear kinetics of hydralazine, probably reflecting saturable first pass metabolism.
After intravenous administration of hydralazine in a dose of 0.3 mg/kg, the steady-state volume of distribution in patients with congestive heart failure was 2.2 L/kg.
Metabolism and Elimination
Metabolism is the main route for the elimination of hydralazine. Negligible amounts of unchanged hydralazine are excreted in urine. Hydralazine is metabolized by acetylation, ring oxidation and conjugation with endogenous compounds including pyruvic acid. Acetylation occurs predominantly during the first pass after oral administration which explains the dependence of the absolute bioavailability on the acetylator phenotype. About 50% of patients are fast acetylators and have lower exposure.
After oral administration of hydralazine, the major circulating metabolites are hydralazine pyruvate hydrazone and methyltriazolophthalazine. Hydralazine is the main pharmacologically active entity; hydralazine pyruvate hydrazone has only minimal hypotensive and tachycardic activity. The pharmacological activity of methyltriazolophthalazine has not been determined. The major identified metabolite of hydralazine excreted in urine is acetylhydrazinophthalazinone.
Absorption and Distribution
Absorption of isosorbide dinitrate from tablets after oral dosing is nearly complete. The average bioavailability of isosorbide dinitrate is about 25%, but is highly variable (10%-90%) due to first-pass metabolism and increases progressively during chronic therapy. Serum concentrations reach their maximum about one hour after ingestion.
The volume of distribution of isosorbide dinitrate is 2 to 4 L/kg. About 28% of circulating isosorbide dinitrate is protein bound.
Under steady-state conditions, isosorbide dinitrate accumulates significantly in muscle (pectoral) and vein (saphenous) wall relative to simultaneous plasma concentrations.
Metabolism and Elimination
Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver and is cleared at a rate of 2 to 4 L/minute with a serum half-life of about 1 hour. Isosorbide dinitrate’s clearance is primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%). Both metabolites have biological activity , especially the 5-mononitrate which has an overall half-life of about 5 hours. The 5-mononitrate is cleared by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronides, and by denitration/hydration to sorbitol. The 2-mononitrate appears to participate in the same metabolic pathways with a half-life of about 2 hours.
Most isosorbide dinitrate is eliminated renally as conjugated metabolites.
Absorption and Bioavailability
Following a single 75-mg oral dose of hydralazine plus 40 mg of isosorbide dinitrate to 19 healthy adults, peak plasma concentrations of hydralazine (88 ng/mL/65 kg) and isosorbide dinitrate (76 ng/mL/65 kg) were reached in 1 hour. The half-lives were about 4 hours for hydralazine and about 2 hours for isosorbide dinitrate. Peak plasma concentrations of the two active metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, were 98 and 364 ng/mL/65 kg, respectively, at about 2 hours. No information is currently available regarding the effect of food on the bioavailability of hydralazine or isosorbide dinitrate from BiDil tablets.
The pharmacokinetics of hydralazine and isosorbide dinitrate, alone or in combination, have not been determined in patients below the age of 18 years.
The pharmacokinetics of hydralazine and isosorbide dinitrate, alone or in combination, have not been determined in patients over 65 years of age.
The effect of renal impairment on the pharmacokinetics of hydralazine has not been determined. In a study with 49 hypertensive patients on chronic therapy with hydralazine in daily doses of 25-200 mg, the daily dose of hydralazine in 19 subjects with severely impaired renal function (creatinine clearance 5-28 mL/min) and in 17 subjects with normal renal function (creatinine clearance >100 mL/min) was not different, suggesting no need for dose adjustment in patients with renal impairment. The dialyzability of hydralazine has not been determined. In three studies, renal insufficiency did not affect the pharmacokinetics of isosorbide dinitrate. Dialysis is not an effective method for removing isosorbide dinitrate or its metabolite isosorbide-5-mononitrate from the body.
The effect of hepatic impairment on the pharmacokinetics of hydralazine alone has not been determined. Isosorbide dinitrate concentrations increase in patients with cirrhosis. There are no studies of hepatic impairment using BiDil.
There are no studies of gender-dependent effects with hydralazine. In a single dose study with isosorbide dinitrate, no gender-dependent differences in the pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites were found.
No pharmacokinetic studies in special populations were conducted with BiDil.
Pharmacokinetic Drug-Drug Interactions
Administration of hydralazine can increase the exposure to a number of drugs including beta blockers.
In healthy males administered a single oral dose of hydralazine 50 mg and propranolol 1 mg/kg, the Cmax and AUC for propranolol increased by about 143% and 77%, respectively. In healthy subjects administered a single oral dose of hydralazine 50 mg and metoprolol 100 mg, the Cmax and AUC for metoprolol increased by about 50% and 30%, respectively. In pre-eclamptic women, multiple doses of hydralazine 25 mg bid and metoprolol 50 mg bid increased the Cmax and AUC for metoprolol by 88% and 38%, respectively.
In healthy males administered single oral doses of hydralazine 25 mg and either lisinopril 20 mg or enalapril 20 mg, Cmax and AUC for lisinopril were each increased by about 30%, but enalapril concentrations were unaffected.
Intravenous co-administration of 0.2 mg/kg hydralazine HCl and 40 mg furosemide in Japanese patients with congestive heart failure resulted in a 21% increase in the clearance of furosemide.
A single dose of 20 mg of isosorbide dinitrate was administered to healthy subjects after pretreatment with 80 mg propranolol tid for 48 hours, resulting in no impact on the pharmacokinetics of isosorbide dinitrate and isosorbide 5-mononitrate.
When single 100-mg oral doses of atenolol were administered 2 hours before isosorbide dinitrate at a 10-mg dose no differences in the pharmacokinetics of isosorbide dinitrate or its mononitrates were observed.
The vasodilating effects of coadministered isosorbide dinitrate may be additive to those of other vasodilators, especially alcohol when administered concomitantly with isosorbide dinitrate.
No pharmacokinetic drug-drug interaction studies were conducted with BiDil.
The basis for the beneficial clinical effects of BiDil is not known. In a small study of patients with chronic heart failure administered single doses of hydralazine 75 mg, isosorbide dinitrate 20 mg, and the combination, the combination elicited a statistically significant decrease in pulmonary capillary wedge pressure compared to hydralazine alone. The increase in cardiac output, renal blood flow and limb blood flow with the combination, however, was not greater than with hydralazine alone. There is no study of hemodynamic effects following multiple dosing.
BiDil or a combination of isosorbide dinitrate and hydralazine hydrochloride was studied in two placebo-controlled clinical trials in 1,692 patients with mild to severe heart failure (mostly NYHA class II and III) and one active control trial (vs. enalapril) in 804 patients.
In the multicenter trial V-HeFT I, the combination of hydralazine and isosorbide dinitrate 75 mg/40 mg qid (n=186) was compared to placebo (n=273) in men with impaired cardiac function and reduced exercise tolerance (primarily NYHA class II and III), and on therapy with digitalis glycosides and diuretics. There was no overall significant difference in mortality between the two treatment groups. There was, however, a trend favoring hydralazine and isosorbide dinitrate, which on retrospective analysis, was attributable to an effect in blacks (n=128). Survival in white patients (n=324) was similar on placebo and the combination treatment.
In a second study of mortality, V-HeFT II, the combination of hydralazine and isosorbide dinitrate 75 mg/40 mg qid was compared to enalapril in 804 men with impaired cardiac function and reduced exercise tolerance (NYHA class II and III), and on therapy with digitalis glycosides and diuretics. The combination of hydralazine and isosorbide dinitrate was inferior to enalapril overall, but retrospective analysis showed that the difference was observed in the white population (n=574); there was essentially no difference in the black population (n=215).
Based on these retrospective analyses suggesting an effect on survival in black patients, but showing little evidence of an effect in the white population, a third study was conducted among black patients with heart failure.
The A-HeFT trial evaluated BiDil vs. placebo among 1,050 self-identified black patients (over 95% NYHA class III) at 169 centers in the United States. All patients had stable symptomatic heart failure. Patients were required to have LVEF ≤ 35% or left ventricular internal diastolic dimension > 2.9 cm/m2 plus LVEF < 45%. Patients were maintained on stable background therapy and randomized to BiDil (n=518) or placebo (n=532). BiDil was initiated at 20 mg isosorbide dinitrate/37.5 mg hydralazine hydrochloride three times daily and titrated to a target dose of 40/75 mg three times daily or to the maximum tolerated dose. Patients were treated for up to 18 months.
The randomized population was 60% male, 1% NYHA class II, 95% NYHA class III and 4% NYHA class IV, with a mean age of 57 years, and was generally treated with standard treatments for heart failure including diuretics (94%, almost all loop diuretics), beta-blockers (87%), angiotensin converting enzyme inhibitors (ACE-I; 78%), angiotensin II receptor blockers (ARBs; 28%), either ACE-I or ARB (93%), digitalis glycosides (62%) and aldosterone antagonists (39%).
The primary end point was a composite score consisting of all-cause mortality, first hospitalization for heart failure, and responses to the Minnesota Living with Heart Failure questionnaire, with the individual components of the composite examined as separate endpoints. The trial was terminated early, at a mean follow-up of 12 months, primarily because of a statistically significant 43% reduction in all-cause mortality in the BiDil-treated group (p=0.012; see Table 1 and Figure 1). The primary endpoint was also statistically in favor of BiDil (p ≤ 0.021). The BiDil-treated group also showed a 39% reduction in the risk of a first hospitalization for heart failure (p<0.001; see Table 1 and Figure 2) and had statistically significant improvement in response to the Minnesota Living with Heart Failure questionnaire, a self-report of the patient’s functional status, at most time points (see Figure 3). Patients in both treatment groups had mean baseline questionnaire scores of 51 (out of a possible 105).
Table 1. Results of A-HeFT (Intent-To-Treat Population)
|Composite score||-0.16±1.93||-0.47±2.04||N/A||N/A||≤ 0.021|
for heart failure
Figure 1: Kaplan-Meier Plot of Time to Death by All Cause in Black Patients (A-HeFT)
Figure 2: Kaplan-Meier Plot of Time to First Hospitalization for Heart Failure in Black Patients (A-HeFT)
Figure 3: Change in Minnesota Living with Heart Failure Score
Effects on survival and hospitalization for heart failure were similar in subgroups by age, gender, baseline disease, and use of concomitant medications, as shown in Figure 4.
Figure 4: Results for Demographic, Baseline Medication and Clinical Characteristic Subgroups in Black Patients (A-HeFT)
Patients treated with BiDil in the A-HeFT study had randomly measured blood pressures on average 3/3 mmHg lower than did patients on placebo. The contribution of the difference in blood pressure to the overall outcome difference is unknown. Whether both hydralazine and isosorbide dinitrate contribute to the overall outcome difference has not been studied in outcome trials. Isosorbide dinitrate and hydralazine have not been systematically studied for the treatment of heart failure as separate agents, and neither drug is indicated for heart failure.