ACE Inhibitor Trandolapril (Mavik) Approved for Hypertension
The FDA has approved a long-acting angiotensin-converting enzyme (ACE) inhibitor – trandolapril (Mavik), marketed by Knoll Pharmaceuticals on license from Roussel Uclaf – for the treatment of mild to moderate hypertension. ACE catalyzes the conversion of angiotensin I to angiotensin II, a potent peripheral vasoconstrictor that also stimulates the secretion of aldosterone. The enzyme also degrades bradykinin, a potent peripheral vasodilator. By inhibiting ACE, trandolapril reduces angiotensin II formation and thus decreases vasoconstriction; it decreases aldosterone secretion and thus increases diuresis and natriuresis; and it increases bradykinin levels and thus promotes vasodilation. Trandolapril has several advantages over similar agents: It can be given once daily; it effectively inhibits both tissue and plasma ACE; it is eliminated via both the liver and the kidneys; and it will be priced below most other ACE inhibitors.
Like other ACE inhibitors, trandolapril (Mavik) significantly reduces blood pressure in hypertensive patients and also reduces the risk of death following myocardial infarction (MI) and the progression to heart failure. During the long-term Danish Trandolapril Cardiac Evaluation (TRACE) study, the drug significantly reduced overall mortality and severe heart failure when given soon after MI. A total of 6676 consecutive patients with MI (confirmed by enzyme studies) were screened and 1749 with echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction 235%) were treated with trandolapril or placebo on days 3 thru 7 following infarction. Follow-up was 24 to 50 months. Trandolapril significantly reduced the risk of death (by 22%, compared with placebo), including death from cardiovascular causes (by 25%) and sudden death (by 24%). The drug also significantly reduced progression to severe heart failure (by 29%) and reduced (nonsignificantly) the risk of recurrent fatal or nonfatal myocardial infarction. The Danish investigators concluded that the reduction in mortality observed in trandolapril-treated patients “should encourage the selective use of ACE inhibition after myocardial infarction.”
As with most other ACE inhibitors, trandolapril (Mavik) is a prodrug that undergoes hepatic metabolism to the active trandolaprilat; absolute bioavailability is 10% as trandolapril and 70% as trandolaprilat. When administered in the fasting state, peak trandolapril levels occur in 0.5 to 1.0 hour and peak trandolaprilat levels in 4 to 10 hours. Food slows the rate but not the extent of absorption. Trandolapril and trandolaprilat are protein bound (65-94%) and eliminated via the kidneys (33%) and liver (66%); there is an initial rapid elimination phase, followed by a prolonged terminal elimination phase (due to plasma and tissue binding to ACE and slow dissociation from the enzyme). The effective accumulation half-life of trandolaprilat is 15 to 24 hours or even longer; steady-state plasma concentrations are reached within four days. Trandolaprilat accumulates in patients with chronic renal failure and creatinine clearance of less than 30 mL/minute.
Trandolapril (Mavik) is very well tolerated. In placebo-controlled clinical trials involving 1067 patients (831 on trandolapril), the most common adverse effects were ACE inhibitor cough (1.9%), dizziness (1.3%), and diarrhea (1%). The drug can cause fetal/neonatal damage and death, so should not be used during pregnancy. Because it has a long half-life, trandolapril can be given once daily, usually in a dose of 1 to 2 mg. Generally, black patients need higher dosages. In four dose-response trials involving 827 patients with mild to moderate hypertension, the minimum effective dose for blacks was 2 mg compared with 1 mg for non-blacks; no further response was observed with doses above 4 mg.
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