Benazepril pharmacokinetics and molecular data

Pharmacokinetics and molecular data
General Characteristics Clinical Pharmacology Pharmacokinetics and Metabolism Pharmacodynamics Hypertension in Adults Hypertension in Pediatric Group

General Characteristics
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is 3-[[1-(ethoxy-carbonyl)-3- phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is:

Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.

Benazeprilat, the active metabolite of Benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. Benazepril is converted to Benazeprilat by hepatic cleavage of the ester group.

Benazepril hydrochloride is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of Benazepril hydrochloride for oral administration. The inactive ingredients are carnauba wax, colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, starch, titanium dioxide, and triacetin. The 10 mg tablet also contains FD&C Red No. 40 aluminum lake. The 20 mg tablet also contains black iron oxide and yellow iron oxide. The 40 mg tablet also contains FD&C Blue No. 2 aluminum lake.

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Mechanism of Action
Benazepril and Benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with Benazepril hydrochloride alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with Benazepril hydrochloride and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium.

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, Benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Benazepril hydrochloride tablets remains to be elucidated.

While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension.

Pharmacokinetics and Metabolism
Following oral administration of Benazepril hydrochloride tablets, peak plasma concentrations of Benazepril are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract.

Cleavage of the ester group (primarily in the liver) converts Benazepril to its active metabolite, Benazeprilat. Peak plasma concentrations of Benazeprilat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of Benazepril is about 96.7% and that of Benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L).

Benazepril is almost completely metabolized to Benazeprilat, which has much greater ACE inhibitory activity than Benazepril, and to the glucuronide conjugates of Benazepril and Benazeprilat. Only trace amounts of an administered dose of Benazepril hydrochloride tablets can be recovered in the urine as unchanged Benazepril, while about 20% of the dose is excreted as Benazeprilat, 4% as Benazepril glucuronide, and 8% as Benazeprilat glucuronide.

The kinetics of Benazepril are approximately dose-proportional within the dosage range of 10-80 mg.

In adults, the effective half-life of accumulation of Benazeprilat following multiple dosing of Benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of Benazeprilat should be reached after 2 or 3 doses of Benazepril hydrochloride given once daily.

The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of Benazeprilat were 1.19 and 1.27, respectively.

Benazepril and Benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of Benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance.

In patients with renal insufficiency, the disposition of Benazepril and Benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance ≤30 mL/min, peak Benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed.

When dialysis was started two hours after ingestion of 10 mg of Benazepril, approximately 6% of Benazeprilat was removed in 4 hours of dialysis. The parent compound, Benazepril, was not detected in the dialysate.

In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of Benazeprilat are essentially unaltered. The pharmacokinetics of Benazepril and Benazeprilat do not appear to be influenced by age.

In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of Benazepril hydrochloride (0.1 to 0.5 mg/kg), the clearance of Benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of Benazeprilat in pediatric patients was around 5 hours, one-third that observed in adults.

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Pharmacodynamics
Single and multiple doses of 10 mg or more of Benazepril hydrochloride tablets cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10 mg dose.

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Hypertension in Adults
Administration of Benazepril hydrochloride tablets to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted.

In single-dose studies, Benazepril hydrochloride tablets lowered blood pressure within 1 hour, with peak reductions achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6-12 /4-7 mmHg. The trough values represent reductions of about 50% of that seen at peak.

Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once daily dose of Benazepril hydrochloride tablets was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10-80 mg). In studies comparing the same daily dose of Benazepril hydrochloride tablets given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.

During chronic therapy, the maximum reduction in blood pressure with any dose is generally achieved after 1-2 weeks. The antihypertensive effects of Benazepril hydrochloride tablets have continued during therapy for at least two years. Abrupt withdrawal of Benazepril hydrochloride tablets has not been associated with a rapid increase in blood pressure.

In patients with mild-to-moderate hypertension, Benazepril hydrochloride tablets 10-20 mg were similar in effectiveness to captopril, hydrochlorothiazide, nifedipine SR, and propranolol.

The antihypertensive effects of Benazepril hydrochloride tablets were not appreciably different in patients receiving high- or low-sodium diets.

In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or no change in heart rate. In normal human volunteers, single doses of Benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

Use of Benazepril hydrochloride tablets in combination with thiazide diuretics gives a blood-pressure-lowering effect greater than that seen with either agent alone. By blocking the renin-angiotensin-aldosterone axis, administration of Benazepril hydrochloride tablets tends to reduce the potassium loss associated with the diuretic.

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Hypertension in Pediatric Group
In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or Benazepril and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on Benazepril. No dose-response was observed for the three doses.

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