Drugs 41 (Suppl. I): 3-10, 1991 0012-6667/91/0 I 00-0003/$4.00/0 © Adis International Limited All rights reserved. DRSUP1954a
Clinical Pharmacology of Cilazapril Cornelis H. Kleinbloesem, 1 Peter van Brummelen, 1 Robert J. Francis 2 and Uff W. Wiegand l I Department of Clinical Research and Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland 2 Roche Products Ltd, Department of Pharmacokinetics and Metabolism, Welwyn Garden City, Hertfordshire, England
Summary
In clinical pharmacology studies, cilazapril, after its bioactivation to cilazaprilat, was characterised as a potent, reversible angiotensin converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours, which is consistent with saturable binding to ACE. Despite the arterial vasodilatation, only slight increases in heart rate occurred during cilazapril administration. Cilazapril had no acute effect on cardiovascular reflexes, and increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close positive correlation was found between the cilazaprilat plasma concentration and degree of ACE inhibition. The potency of cilazaprilat, defined as the concentration of cilazaprilat causing 50% inhibition of ACE, was approximately I ILg/L plasma. In short term studies in patients with hypertension, it appeared that more than 90% inhibition of plasma ACE was needed to obtain blood pressure reduction. Results of various dose·response studies established the indirect relationship between dose, the plasma concentration of the drug, and the blood pressure response, and identified the dose producing the maximal effect to be 5mg. Cilazapril inhibited ACE for a relatively long period which was extended in patients with severe chronic renal impairment or hepatic failure. In these patients a reduction of the dose and/or less frequent administration is recommended. There was no clinically relevant interaction of cilazapril with food, furosemide (frusemide), digoxin or coumarins. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril, and an additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with indomethacin and cilazapril might occur, potentially reducing the blood pressure-lowering effect of cilazapril. In general, cilazapril was well tolerated.
Since the introduction of captopril as the first orally active angiotensin converting enzyme (ACE) inhibitor for use in the treatment of arterial hypertension and congestive heart failure, new substances of this class have been developed (Brunner et al. 1985), one of which is cilazapril (Ro 31-2848). Like other ACE inhibitors such as enalapril and
ramipril (Williams 1988), cilazapril is a prodrug that has to be hydrolysed in vivo to its active form, the diacid cilazaprilat (Williams et al. 1989a). Preclinical in vitro and in vivo studies have shown that cilazapril is one of the most potent ACE inhibitors available and that it lowers blood pressure by reducing total peripheral resistance, withoutinflu-
Drugs 41 (Suppl. 1) 1991
4
encing cardiovascular reflexes (Fischli et al. 1989; Waterfall 1989).
1. Pharmacokinetics The pharmacokinetic properties of cilazapril have been extensively studied (Fasanella d'Amore et al. 1987; Fillastre et al. 1989; Francis et al. 1987; Massarella et al. 1989a; Meredith et al. 1989; Rosenthal et al. 1989; Williams et al.1989a). In healthy volunteers the absorption of cilazapril and hydrolysis to cilazaprilat occurred relatively rapidly, and dose proportional maximal plasma cilazaprilat concentrations were seen between 1 and 3 hours after oral intake of doses ranging from 0.5 to lOmg (Francis et al. 1987; Massarella et al. 1989a). Thereafter, the decline in plasma cilazaprilat concentrations followed a biphasic pattern, with an initial rapid half-life of approximately 1.5 hours and a prolonged terminal half-life of approximately 30 to 50 hours (fig. 1). During the latter phase, there was only slight dose dependency, suggesting that the pharmacokinetics of cilazapril are nonlinear. These findings have been explained by Francis et al. 1987 on the basis of saturable binding of cilazaprilat to ACE. Cilazaprilat is the only major me-
tabolite of cilazapril, and there is essentially no further metabolism of cilazaprilat. In contrast to some other ACE inhibitors, including captopril, the systemic bioavailability of a therapeutic dose of cilazapril was not influenced to a clinically significant extent by the intake of food (Massarella et al. 1989b). The pharmacokinetics of cilazapril in patients with hypertension were similar to those in healthy volunteers (Meredith et al. 1989). The effect of age was also relatively small and not clinically relevant (Williams et al. 1989b). Like most ACE inhibitors, cilazaprilat is primarily eliminated by renal excretion (Williams et al. 1989a) and, as a consequence, therapeutic doses of cilazapril should be reduced in patients with advanced renal failure (Fillastre et al. 1989). In patients with severe liver cirrhosis, the pharmacokinetics of cilazapril and cilazaprilat were changed, resulting in longer-lasting ACE inhibition accompanied by a prolonged antihypertensive effect. In the unlikely event that patients with liver cirrhosis should require treatment with cilazapril, therapy should be initiated with caution. Because ACE inhibitors are increasingly used in the treatment of congestive heart failure, the influence of this condition on the pharmacokinetics of cilazapril has also been studied. In patients with
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Clinical Pharmacology of Cilazapril Cornelis H. Kleinbloesem, 1 Peter van Brummelen, 1 Robert J. Francis 2 and Uff W. Wiegand l I Department of Clinical Research and Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland 2 Roche Products Ltd, Department of Pharmacokinetics and Metabolism, Welwyn Garden City, Hertfordshire, England
Summary
In clinical pharmacology studies, cilazapril, after its bioactivation to cilazaprilat, was characterised as a potent, reversible angiotensin converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours, which is consistent with saturable binding to ACE. Despite the arterial vasodilatation, only slight increases in heart rate occurred during cilazapril administration. Cilazapril had no acute effect on cardiovascular reflexes, and increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close positive correlation was found between the cilazaprilat plasma concentration and degree of ACE inhibition. The potency of cilazaprilat, defined as the concentration of cilazaprilat causing 50% inhibition of ACE, was approximately I ILg/L plasma. In short term studies in patients with hypertension, it appeared that more than 90% inhibition of plasma ACE was needed to obtain blood pressure reduction. Results of various dose·response studies established the indirect relationship between dose, the plasma concentration of the drug, and the blood pressure response, and identified the dose producing the maximal effect to be 5mg. Cilazapril inhibited ACE for a relatively long period which was extended in patients with severe chronic renal impairment or hepatic failure. In these patients a reduction of the dose and/or less frequent administration is recommended. There was no clinically relevant interaction of cilazapril with food, furosemide (frusemide), digoxin or coumarins. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril, and an additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with indomethacin and cilazapril might occur, potentially reducing the blood pressure-lowering effect of cilazapril. In general, cilazapril was well tolerated.
Since the introduction of captopril as the first orally active angiotensin converting enzyme (ACE) inhibitor for use in the treatment of arterial hypertension and congestive heart failure, new substances of this class have been developed (Brunner et al. 1985), one of which is cilazapril (Ro 31-2848). Like other ACE inhibitors such as enalapril and
ramipril (Williams 1988), cilazapril is a prodrug that has to be hydrolysed in vivo to its active form, the diacid cilazaprilat (Williams et al. 1989a). Preclinical in vitro and in vivo studies have shown that cilazapril is one of the most potent ACE inhibitors available and that it lowers blood pressure by reducing total peripheral resistance, withoutinflu-
Drugs 41 (Suppl. 1) 1991
4
encing cardiovascular reflexes (Fischli et al. 1989; Waterfall 1989).
1. Pharmacokinetics The pharmacokinetic properties of cilazapril have been extensively studied (Fasanella d'Amore et al. 1987; Fillastre et al. 1989; Francis et al. 1987; Massarella et al. 1989a; Meredith et al. 1989; Rosenthal et al. 1989; Williams et al.1989a). In healthy volunteers the absorption of cilazapril and hydrolysis to cilazaprilat occurred relatively rapidly, and dose proportional maximal plasma cilazaprilat concentrations were seen between 1 and 3 hours after oral intake of doses ranging from 0.5 to lOmg (Francis et al. 1987; Massarella et al. 1989a). Thereafter, the decline in plasma cilazaprilat concentrations followed a biphasic pattern, with an initial rapid half-life of approximately 1.5 hours and a prolonged terminal half-life of approximately 30 to 50 hours (fig. 1). During the latter phase, there was only slight dose dependency, suggesting that the pharmacokinetics of cilazapril are nonlinear. These findings have been explained by Francis et al. 1987 on the basis of saturable binding of cilazaprilat to ACE. Cilazaprilat is the only major me-
tabolite of cilazapril, and there is essentially no further metabolism of cilazaprilat. In contrast to some other ACE inhibitors, including captopril, the systemic bioavailability of a therapeutic dose of cilazapril was not influenced to a clinically significant extent by the intake of food (Massarella et al. 1989b). The pharmacokinetics of cilazapril in patients with hypertension were similar to those in healthy volunteers (Meredith et al. 1989). The effect of age was also relatively small and not clinically relevant (Williams et al. 1989b). Like most ACE inhibitors, cilazaprilat is primarily eliminated by renal excretion (Williams et al. 1989a) and, as a consequence, therapeutic doses of cilazapril should be reduced in patients with advanced renal failure (Fillastre et al. 1989). In patients with severe liver cirrhosis, the pharmacokinetics of cilazapril and cilazaprilat were changed, resulting in longer-lasting ACE inhibition accompanied by a prolonged antihypertensive effect. In the unlikely event that patients with liver cirrhosis should require treatment with cilazapril, therapy should be initiated with caution. Because ACE inhibitors are increasingly used in the treatment of congestive heart failure, the influence of this condition on the pharmacokinetics of cilazapril has also been studied. In patients with
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