Rj MacFadyen

Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships. An overview.

SummaryThe conventional pharmacokinetic profile of the angiotensin converting enzyme (ACE) inhibitor, enalapril, is a lipid-soluble and relatively inactive prodrug with good oral absorption (60 to 70%), a rapid peak plasma concentration (1 hour) and rapid clearance (undetectable by 4 hours) by de-esterification in the liver to a primary active diacid metabolite, enalaprilat.Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites. The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects.Renal impairment [particularly creatinine clearance <20 ml/min (<1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.Conventional pharmacokinetic approaches have recently been extended by more detailed descriptions of the nonlinear binding of enalaprilat to ACE in plasma and tissue sites. As a result of these new approaches, there have been significant improvements in the characterisation of concentration-time profiles for single-dose administration and the translation to steady-state. Such improvements have further importance for the accurate integration of the pharmacokinetic and pharmacodynamic responses to enalapril(at) in a concentration-effect model. This model is able to characterise the concentration-effect relationship in individual recipients of the drug and predict the antihypertensive responses to dosage alterations.Therapeutic use of enalapril has recently expanded to include heart failure. In this condition, responses to enalapril may be mediated by different effector systems in different organs and may occur at different concentration ranges to those observed during treatment of hypertension. However, similar concentration-effect analyses are still relevant. After almost 15 years of clinical use, the therapeutic applicability of enalapril continues to expand and detailed pharmacokinetic description of the agent remains an integral component of this expansion.

Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure.

We previously demonstrated differing blood pressure (BP) responses to the first dose of angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF). We wished to confirm the disparate responses to the first dose of these agents, study the response to repeated dosing, and explore possible explanations (slow, tight binding, and steric hindrance) for the phenomenon. Forty-eight elderly patients (aged 51-85 years) with stable CHF were studied for 48 hours. Groups (n = 12) received one of the following: (a) perindopril 2 mg orally (p.o.) + placebo intravenously (i.v.) (day 1) and perindopril 2 mg p.o. (day 2); (b) enalapril 2.5 mg p.o. + placebo i.v. (day 1) and enalapril 2.5 mg p.o. (day 2); (c) placebo p.o. + perindopril at 0.167 mg i.v. (day 1) and perindopril 2 mg p.o. (day 2); or (d) placebo p.o. + placebo i.v. (day 1) and placebo p.o. (day 2). Supine BP was measured on day 1. On day 2, BP was recorded by ambulatory BP monitor. Blood samples were taken at baseline and at intervals during the 48-h study period for estimation of neurohumoral parameters. Inhibition of the renin-angiotensin system (RAS) was estimated by plasma ACE inhibition and also by the ratio of angiotensin II (Ang II)/Ang I + Ang II. On day I, enalapril 2.5 mg caused a greater decrease in BP than did placebo response between 6 and 9 h postdose. Perindopril 2 mg produced a profile of BP response similar to that of placebo. Ambulatory BP on day 2 was consistently lower with enalapril as compared with perindopril. Profiles of plasma ACE inhibition were similar with each active therapy. Enalapril therapy produced a greater increase in plasma renin activity (PRA) than did other treatments. There was no temporal dissociation between plasma ACE inhibition and profile of Ang peptides for any treatment. We have confirmed the disparate BP responses to perindopril and enalapril in CHF. We noted no evidence of slow, tight binding or steric hindrance to explain these differences.

Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man.

In a dose-ranging study, the angiotensin type I receptor antagonist losartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low sodium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days before study. On the fourth day, subjects (n = 12) received placebo and three active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-blind, three-panel, dose-ranging design. On the study day, 24-h urinary sodium excretion was 10–20 mmol Na, with an increase in renin and aldosterone levels at baseline. Dose-dependent decreases in supine and erect blood pressures (BP) were statistically significant for 50 and 100 mg and were associated with a modest increase in supine heart rate (HR) at the higher dose. The peak BP decreases observed suggested that the highest dose studied (100 mg) was not necessarily the maximal response. Active treatments caused no increase in the sodium loss on the study day. Renin was significantly increased by doses >10 mg in a dose-dependent fashion but there was little change in plasma aldosterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms were uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.

Haemodynamic and renal responses to oral losartan potassium during salt depletion or salt repletion in normal human volunteers.

We examined the haemodynamic and renal response to oral losartan potassium (100 mg) during activation of the renin system in humans. Eight healthy volunteers followed a low-salt (40 mmol sodium) diet for 4 days on four occasions 2 weeks apart. Double-blind salt depletion was achieved by 3-day administration of frusemide (40 mg twice daily, b.i.d.) with placebo salt replacement, salt repletion by placebo frusemide (b.i.d.), and active salt replacement (100 mmol/day). On day 4, subjects received randomised double-blind placebo or losartan. Prestudy salt depletion was associated with nonsignificant decreases in serum sodium (138 +/- 2 mM), potassium (3.5 +/- 0.2 mM) and increased urea (6.5 +/- 1.1 mM), and creatinine (91 +/- 6 microM) as compared with screening. Prestudy (day 3) 24-h urinary volume was similar during deplete preparation (placebo 1.707 +/- 0.81 L, losartan 1.509 +/- 0.626 L) or deplete preparation (placebo 1.726 +/- 0.5 L, losartan 1.764 +/- 0.52 L), but sodium excretion was greater during replete preparation. Salt replete supine blood pressure (BP) profiles showed little effect of losartan (mean maximal supine BP -9 +/- 6 mm Hg) as compared with placebo (-1 +/- 4 mm Hg), with a similar relative result for erect BP. After salt depletion, losartan caused a greater response in both supine (-24 +/- 9) and erect (-33 +/- 15) BP than did placebo (supine -12 +/- 5, erect -14 +/- 9). In this protocol after salt depletion, losartan caused a transient increase in urea and creatinine (143 +/- 40 microML) 8 h after dosing as compared with placebo (105 +/- 13 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-ranging study of the angiotensin II receptor antagonist irbesartan (SR 47436/BMS-186295) on blood pressure and neurohormonal effects in salt-deplete men.

We characterised the blood pressure (BP) and hormonal responses to the oral angiotensin II (Ang II) receptor antagonist irbesartan (SR47436/BMS-186295) or placebo in normal men with an activated renin-angiotensin system (RAS) during salt depletion. We also evaluated safety and tolerability. Twelve healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Six different single oral doses of irbesartan (1, 5, 10, 25, 50, and 100 mg) were administered double-blind in a three-panel, dose escalation with placebo randomised in each panel. Supine and erect BP and heart rate (HR), serum and urinary electrolytes: plasma renin activity (PRA), and Ang II were measured at intervals. Urinary electrolytes were measured for the 24-h period before dosing (to confirm salt depletion) and for 24 h afterward. No drug-related side effects were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with irbesartan from 10 mg and beyond, with no change in HR. Supine mean arterial pressure (MAP) decreased by 18.8 mm Hg. There was a dose-related reactive increase in PRA (to 35 ng/ml/h) and Ang II (to 450 pg/ml) with irbesartan. Irbesartan is an orally active AT1 receptor antagonist. In salt-deplete normal men, it has a dose-related haemodynamic, hormonal, and electrolyte profile characteristic of AT1 antagonists. The dose range studied did not show a plateau or maximum effect.

Perindopril : a review of its pharmacokinetics and clinical pharmacology

Perindopril is an orally active, non-thiol angiotensin-converting enzyme (ACE) inhibitor, which in doses of 4 to 8mg is effective in the control of essential hypertension. As monotherapy it is as effective as once-daily atenolol and possibly more effective than twice-daily captopril. A synergistic response has been noted when perindopril is combined with a thiazide diuretic. Maximal pharmacodynamic effects (ACE inhibition, increase in plasma renin activity and angiotensin I, reduction in aldosterone and angiotensin II and blood pressure) are seen 4 to 6 hours after dosing, with substantial effects still present at 24 hours. Perindopril is a prodrug which requires de-esterification to perindoprilat for useful ACE inhibition. Maximal plasma perindoprilat concentrations are reached 2 to 6 hours after oral administration of perindopril, and 70% of the active metabolite is cleared by the kidneys. The other major metabolite of perindopril is an inactive glucuronide. Ageing is associated with increased serum perindoprilat concentrations, which are probably caused by a combination of enhanced conversion to the active metabolite and diminished renal clearance. Compensated cirrhosis does not appear to have an independent effect. There is little published experience of the use of perindopril in patients with cardiac failure or other cardiac disease, but preliminary evidence would support the general value of this class of agent as adjunctive therapy.

Responses to an orally active renin inhibitor, remikiren (Ro 42-5892), after controlled salt depletion in humans.

Summary The biological effects of dose-dependent inhibition of renin have rarely been extensively studied after oral (p.o.) dosing in humans. We studied remikiren (Ro42–4892), a selective renin inhibitor, in normal volunteers after activation of the renin-angiotensin system (RAS) based on salt depletion. Twelve normal men (28 ± 9 years, 77 ± 10 kg), comprising three consecutive dose panels of 4 subjects, received four treatments, double-blind and randomised 2 weeks apart: panel I, placebo (P). or 30. 100. and 300 mg. remikiren: panel II. placebo or 300. 600 mg, 1,000; panel III, placebo or 30, 600, and 1,000 mg. The RAS was activated by 40 mmol/day sodium diet plus frusemide (40 mg BDS), for 3 days before each study day. Data (mean ± SD) were examined by repeated-measures analysis of variance (ANOVA). RAS activation was confirmed by 24-h urinary sodium excretion (screen, 142 ± 74 mmol/24 h: prestudy, 66 ± 33. 59 ± 41, 78 ± 4. 73 ± 30 mmol/24 h) and increase in plasma renin activity (PRA) (screen, 0.8 ± 0.3 ng AI/ml/h; before dosing. P, 6.5 ± 3.1: 30 mg. 8.2 ± 3; 100 mg. 9.4 ± 5.7: 300 mg. 6.5 ± 2.4; 600 mg. 5.2 ± 2: 1,000 mg. 6.2 ± 4.4 ng AI/ml/h). PRA was reduced in dose dependently (mean minimal activity: 30 mg 1.4 ± 1.2: 100 mg. 1.6 ± 1: 300 mg, 0.1 ± 0.1,600 mg, 0.1 ± 0.1:1,000 mg, 0.01 ± 0.02), and active renin was increased (mean maximal active renin; 30 mg. 182 ± 186; 100 mg. 185 ± 83: 300 mg. 252 ± 240; 600 mg. 262 ± 100, 1.000 mg. 1.417 ± 2.008 pg/ml). Maximal effects were noted soon after dosing for PRA (30 mg. 1.1 ± 0.3: 100 mg. 1 ± 0; 300 mg. 1 ± 0; 600 mg. 1.3 ± 0.4; 1.000 mg. 1.3 ± 0.4 h) but slower for increase in active renin (30 mg. 4.6 ± 1.3. 100 mg. 3 ± 1.4; 300 mg. 1.8 ± 1.6: 600 mg. 2.8 ± 1.5; 1,000 mg. 3.4 ± 1.4 h). Despite evidence of biochemical effect, supine blood pressure (BP) was not significantly affected by active treatment. Erect BP did show a significant decrease from pretreatment values, but only after 1,000 mg remikiren 1 h after dosing (P. baseline, 116 ± 12/68 ± 7: 1 h, 112 ± 8/65 ± 7; 1.000 mg. baseline, 114 ± 12/65 ± 7; 1 h, 96 ± 9/50 ± 18). Drug concentrations showed a wide dose-related spectrum of mean maximal concentrations (30 mg. 1.07 ± 1.64; 100 mg, 2.17 ± 1.38; 300 mg. 28.88 ± 16.95; 600 mg. 67.76 ± 36.06: 1.000 mg. 136.9 ± 156 ng/ml). Values for Tmax were generally observed soon after dosing and were not clearly dose related (30 mg. 0.5 ± 0.5; 100 mg. 0.56 ± 0.77; 300 mg, 0.66 ± 0.51: 600 mg. 0.44 ± 0.11; 1,000 mg. 0.94 ± 0.63 h). Remikiren is enzymatically active after p.o. administration in humans in a dose-dependent manner. Only the dose of 1.000 mg reduced BP in salt-deplete subjects. Haemodynamic effects are therefore demonstrable but are slight, dissociated from RAS inhibition in blood, despite confirmed activation of the RAS. BP changes parallel the pharmacokinetic profile. The latter is unlikely to permit once daily dosing with 24-h effect. Higher doses and or controlled-release p.o. formulations or alternative routes of administration would be required to achieve antihypertensive efficacy. Owing to the selective nature of renin inhibition, a separate profile of efficacy and response in hypertensive patients is unlikely.

Differential effects of ACE inhibiting drugs: Evidence for concentration‐, dose‐, and agent‐dependent responses

Clinical Pharmacology and Therapeutics (1993) 53, 622–629; doi:10.1038/clpt.1993.82

Neurohormonal and blood pressure responses to low-dose infusion of an orally active renin inhibitor, Ro 42-5892, in salt-replete men

Summary: Renin inhibitors are an alternative means of blockade of circulating and tissue-based renin–angiotensin systems (RAS). We studied a new renin inhibitor, Ro 42-5892, by low-dose (0.1 mg/kg) intravenous (i.v.) infusion in 10 min (fast) or 6 h (slow) or placebo in a double-blind cross-over study to assess the relationship between drug concentration and response. Fasting salt-replete normotensive male volunteers (n = 9) aged 18–32 years were studied supine. There were no significant changes in blood pressure (BP) or heart rate (HR) between drug and placebo infusion. Drug concentration peaked (482 ± 140 ng/ml) at the end of the fast infusion or showed a sustained plateau (25.9 ± 6.1 ng/ml) with the slow infusion (mean time to peak 121 ± 99 min). Both fast (135.2 ± 26 ng/ml/h2) and slow (121.0 ± 31.1 ng/ml/h2) infusions had similar area under the curve (AUC)0–24-values. Plasma renin activity (PRA) was dramatically reduced by both strategies, but AUC0–10 for PRA was significantly less for slow (1.7 ± 0.6 ngAI/ml/h2) than fast (4.9 ± 2.5 ngAI/ml/h2) infusions. Mean peak plasma active renin (AR) concentration was increased by both fast (102.2 ± 65.9 pg/ml) and slow (195.2 ± 110.5 pg/ml) infusions as compared with placebo (49.9 ± 18.6 pg/ml). Similarly, AUC0–10 for AR was greater for slow (990.2 ± 582.1 pg/ml/h) than fast (512.4 ± 189.4 pg/ml/h) infusions. Plasma angiotensin-converting enzyme (ACE) activity was unaltered. Our results indicate that protracted low concentrations of Ro 42-5892 may provide more effective and long-lasting inhibition of renin. Clinical use of oral sustained release or transcutaneous formulations may be valuable in cardiovascular diseases.

Role of the circulating and tissue-based renin-angiotensin system in the development of heart failure: implications for therapy.

The renin-angiotensin system (RAS) is believed to play a central role in the pathophysiology of heart failure. However, there is a wide variability in plasma renin levels in patients with heart failure, and normal plasma renin activity has been documented in patients with mild or compensated disease. Recent evidence has demonstrated the existence of endogenous RAS in a number of tissues associated with cardiovascular homeostasis. It is possible that these tissue RAS are activated in the early stages of heart failure when plasma renin activity is normal, and therefore contribute to the progression of this condition. Angiotensin-converting enzyme (ACE) inhibitors reduce both circulating and tissue RAS activity. They are of symptomatic benefit and reduce the mortality associated with heart failure. A number of large studies initiated to investigate the effects of the ACE inhibitor enalapril in patients with all degrees of heart failure have been published recently. These studies show that addition of this drug to therapy significantly decreases patient morbidity and mortality, an effect which is most likely due to the suppression of circulating and tissue RAS activity this agent affords. The relationship of the profile of hormonal suppression seen with enalapril and drug dosage to observed beneficial effects on morbidity or mortality is unclear. Given the large range of alternative ACE inhibitors available, their variable structure, potency and duration of action, the potential for differences between agents needs further consideration. Although direct comparative studies are rare, there is a body of work suggesting that such differentiation may be present and may be of clinical significance.