Fixed dose combination of delapril, an inhibitor of the angiotensin conversion enzyme, and manidipine, a dyhydropyridine calcium-antagonist with antihypertensive activity and nephroprotecting properties. The combination of these active ingredients through complementary mechanisms of action produces a synergistic antihypertensive effect, reducing blood pressure in a greater measure than with the single constituents.
Delapril brings about the antihypertensive effect by inhibiting the conversion of Angiotensin I to Angiotensin II; due to the lipophilic effect of the combination, the inhibition mainly occurs at the level of the vessel wall. Delapril reduces the peripheral resistances and increases sodium and water elimination by blocking the renin-angiotensin-aldosterone system.
Manidipine, whose characteristic is a long-lasting antihypertensive effect, shows vascular selectivity for the renal district, increasing renal blood flow and reducing vascular resistances of afferent and efferent arterioles with reduction of intraglomerular pressure. The effects on the renal haemodynamics allow the glomerular filtering fraction to be maintained over time. This characteristic is associated to the drug diuretic properties, due to the inhibition of water and sodium reabsorption at the tubular level.
The combination of the two active ingredients (delapril/manidipine) produced, in pharmacodynamic studies, antihypertensive effects significantly stronger and longer lasting compared to the single components. In hypertensive patients, a clinically significant reduction of blood pressure lasted throughout 24 hours after a single daily dose.
Pharmacokinetic studies showed that delapril, after rapid absorption by the gastrointestinal tract, is metabolised in the active forms of delapril diacid (MI), and 5-idroxy-delapril diacid (MIII).
The main serum metabolite is MI, followed by MIII, while serum levels of MII, a cyclic inactive metabolite, and unchanged delapril are reduced. Metabolite MI shows, compared to the other circulating species, the highest blood concentration values with a peak time of 1.3-1.6 hr. Delapril absorption rate is modestly reduced by the presence of food in the gastrointestinal tract.
Since delapril is partly metabolised to active forms in the liver, in subjects with hepatic failure this conversion might be slowed down. There is no clinical experience in patients with hepatic failure or with hepatic cirrhosis.
Delapril and MI bind to human serum proteins by more than 95%. A pharmacokinetic study at steady state in the elderly did not reveal accumulation of delapril.
Approximately 60% of the product is eliminated in the 24-hour urine, mainly in the form of metabolites MI and MIII and in minimum amounts as unchanged delapril and MII. Fecal excretion is complemental to the urinary one. Repeated administration gives no rise to delapril and metabolites' accumulation phenomena. Studies in special patient populations have shown that the urinary excretion of unmodified delapril and its metabolite MI is considerably reduced in patients with severe renal function impairment (blood creatinine >3 mg/dl).
After oral administration, manidipine shows a plasma concentration peak at 2-3.5 hours, and undergoes a first-passage effect. Manidipine absorption is enhanced by the presence of food in the gastrointestinal tract.
The binding with plasma proteins is of 99%. The product is widely distributed to tissues and widely metabolised, mainly at hepatic level.
Since manidipine is metabolised at the hepatic level, a reduction in the liver metabolic function can modify its pharmacokinetics. Patients with mild hepatic impairment did not exhibit significantly altered pharmacokinetics in respect to healthy subjects, while trend towards higher systemic exposure was observed in patients with more severe hepatic impairment.
Elimination chiefly occurs in feces (63%) and partially in urine (31%). After repeated administrations no accumulation phenomenon is observed. Manidipine did not show different pharmacokinetics in patients with renal insufficiency in comparison to healthy volunteers even in case of severe renal insufficiency. In elderly patients the administration of manidipine is associated with increased plasma levels and a longer plasma half-life.
Concomitant administration of delapril and manidipine did not induce any mutual interference on the single components' pharmacokinetic characteristics. No accumulation of the two active ingredients was observed after repeated administration of the combination. After repeated administration of the combination in the elderly the exposure to the single components was higher in comparison to young subjects expecially for manidipine and metabolite MI of delapril.
The combination showed a low acute toxicity and after repeated administration in rats and dogs adequate safety margins relating to the recommended therapeutic doses were obtained.
The toxic manifestations observed at high doses (mainly decrease in body weight and increase in spontaneous incidence of renal changes in rats; induction of reversible gingival hypertrophy in dogs) were associated to exaggerated pharmacodynamic effects and were consistent with information already known for the single components, this excluding toxicologic interactions.
Reproduction toxicity studies have been conducted in rats and rabbits receiving oral doses of the combination of delapril/mandipine (ratio 3:1).
In a rat fertility and early embryonic developmental study embryo/fetotoxic effects, including a higher incidence of displaced testis, kinked urether, incomplete ossification of the sternum, and reduced number of live fetuses, were observed. The adverse effects appeared at the lowest dose level of 12 mg/kg/day, the maternal NOAEL. The exposure levels of the combination at this dose was lower than the human exposure levels at the recommended clinical dose. A NOAEL for embryo-/fetotoxic effects could not be established.
In a pre-/postnatal study in rats effects on the fetus, including increase in pup loss and decrease in body weight gain, were observed at the highest and maternal toxic dose level. Difficulties in parturition were also seen in rats at higher dose levels.
In rabbits no substance-induced effects on embryo-foetal development were observed.
No mutagenicity potential was evidenced with the combination and the single components and the available data for the single components do not show potential risks of oncogenicity in man.
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