Altace - Clinical Pharmacology

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The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2Ð 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elim-ination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9Ð 18 hours.

The terminal elimination phase has a prolonged half-life (> 50 hours) and probably represents the binding/ dissociation kinetics of the ramiprilat/ ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5Ð 10 mg, the half-life of ramiprilat concentrations within the ther-apeutic range was 13Ð 17 hours. After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose.

Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses (2.5 mg), but the difference is clinically insignificant. In patients with creatinine clearance less than 40 ml/ min/ 1.73m 2 , peak levels of ramiprilat are approximate-ly doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3Ð 4 times as large as it is in patients with normal renal function who receive similar doses.

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance less than 40 ml/ min/ 1.73m 2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations. (See DOSAGE AND ADMINISTRATION.)

In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, pos-sibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.