CLINICAL PHARMACOLOGY

Mechanism of Action: ACEON® (perindopril erbumine) Tablets is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.

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

While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblacks, a finding consistent with previous experience of other ACE inhibitors.

After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.

Pharmacokinetics: Oral administration of ACEON® (perindopril erbumine) Tablets results in its rapid absorption with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after perindopril administration. The presence of food in the gastrointestinal tract does not affect the rate or extent of absorption of perindopril but reduces bioavailability of perindoprilat by about 35%. (See PRECAUTIONS: Food Interactions.)

With 4, 8 and 16 mg doses of ACEON® Tablets, Cmax and AUC of perindopril and perindoprilat increase in a linear and dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.

Perindopril exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1.0 hours. At very low plasma concentrations of perindopril (<3 ng/mL), there is a prolonged terminal elimination half-life, similar to that seen with other ACE inhibitors, that results from slow dissociation of perindopril from plasma/tissue ACE binding sites. Perindopril does not accumulate with a once-a-day multiple dosing regimen. Mean total body clearance of perindopril is 219 to 362 mL/min and its mean renal clearance is 23.3 to 28.6 mL/min.

Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril.

The active metabolite, perindoprilat, also exhibits multiexponential pharmacokinetics following the oral administration of ACEON® Tablets. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once-daily dosing with perindopril, perindoprilat accumulates about 1.5 to 2.0 fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.

Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.

At usual antihypertensive dosages, little radioactivity (<5% of the dose) was distributed to the brain after administration of 14C-perindopril to rats.

Radioactivity was detectable in fetuses and in milk after administration of 14C-perindopril to pregnant and lactating rats.

Elderly Patients: Plasma concentrations of both perindopril and perindoprilat in elderly patients (>70 yrs) are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat. (See PRECAUTIONS: Geriatric Use.)

Heart Failure Patients: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC. (See DOSAGE AND ADMINISTRATION.)

Patients with Renal Insufficiency: With perindopril erbumine doses of 2 to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that of 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.

In a limited number of patients studied, perindopril dialysis clearance ranged from 41.7 to 76.7 mL/min (mean 52.0 mL/min). Perindoprilat dialysis clearance ranged from 37.4 to 91.0 mL/min (mean 67.2 mL/min). (See DOSAGE AND ADMINISTRATION.)

Patients with Hepatic Insufficiency. The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.

Pharmacodynamics: In placebo-controlled studies of perindopril monotherapy (2 to 16 mg q.d.) in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 to 16 mg lowered blood pressure. The 8 and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. The magnitude of the blood pressure effect was similar in the standing and supine positions, generally about 1 mm Hg greater on standing. In these studies, doses of 8 and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once-daily and twice-daily dosing were compared, the B.I.D. regimen was generally slightly superior, but by not more than about 0.5 to 1 mm Hg. After 2 to 16 mg doses of perindopril, the trough mean systolic and diastolic blood pressure effects were approximately equal to the peak effects (measured 3 to 7 hours after dosing.). Trough effects were about 75 to 100% of peak effects. When perindopril was given to patients receiving 25 mg HCTZ, it had an added effect similar in magnitude to its effect as monotherapy, but 2 to 8 mg doses were approximately equal in effectiveness. In general, the effect of perindopril occurred promptly, with effects increasing slightly over several weeks.

In hemodynamic studies carried out in animal models of hypertension, blood pressure reduction after perindopril administration was accompanied by a reduction in peripheral arterial resistance and improved arterial wall compliance. In studies carried out in patients with essential hypertension, the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no significant changes in heart rate or glomerular filtration rate. An increase in the compliance of large arteries was also observed, suggesting a direct effect on arterial smooth muscle, consistent with the results of animal studies.

Formal interaction studies of ACEON® Tablets have not been carried out with antihypertensive agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering ACEON® Tablets with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system. A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON® Tablets. (See PRECAUTIONS: Drug Interactions.)

In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these patients.

The effectiveness of ACEON® Tablets was not influenced by sex and it was less effective in blacks than in nonblacks. In elderly patients (³60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the difference was not significant.