RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection.

BACKGROUND: The effects of three doses of RAD (40-O-[2-hydroxyethyl]-rapamycin), a novel macrolide with potent immunosuppressive and antiproliferative properties, on the incidence and severity of acute rejection episodes as well as its tolerability were evaluated in a dose-ranging study in de novo renal transplant recipients. METHODS: In this double-blind, parallel group, multicenter study, recipients were randomized to receive 1 mg, 2 mg, or 4 mg/day of RAD in combination with Neoral (cyclosporine, USP MODIFIED) and corticosteroids. The incidence and severity of biopsy-proven acute rejection episodes, graft survival, patient survival, infection rates, laboratory measurements, and adverse events were compared across groups after 6 months of therapy. RESULTS: Among the 103 recipients, patients receiving 1, 2, or 4 mg/day experienced a 32.4%, 14.7%, or 25.7% incidence of biopsy-proven acute rejection episodes within the first 6 months posttransplantation, respectively. Even though the study was not powered to demonstrate efficacy, the incidence of moderate and severe acute rejection episodes was found to be significantly lower among patients in the 2 mg and 4 mg/day groups than in the 1 mg/day group (P=0.002 and P=0.006, respectively). Overall graft and patient survival rates were excellent. RAD was generally well tolerated. Although blood lipid levels increased in all groups, changes were manageable with lipid-lowering agents and did not warrant discontinuation of study medication. The incidence of viral and fungal infections was low; however, it was higher among recipients treated with 4 mg/day. CONCLUSIONS: In combination with Neoral and corticosteroids, RAD doses of 2 mg and 4 mg/day resulted in lower rates of acute rejection episodes and efficacy failure than the 1 mg/day dose and were significantly more effective in reducing the severity of rejection. Large-scale, controlled, follow-up studies are currently in progress to confirm these initial findings.

Dose-dependent effects of the renin inhibitor zankiren HCl after a single oral dose in mildly sodium-depleted normotensive subjects.

BACKGROUND: Zankiren HCl (A-72517) is a potent renin inhibitor shown to have substantial bioavailability in several animal species and to produce dose-related reductions in blood pressure, plasma renin activity, and angiotensin II (Ang II) in salt-depleted dogs. The present study was designed to evaluate the hemodynamic effects of oral zankiren HCl administration in healthy volunteers and to characterize the response of the renin-angiotensin system (RAS) to specific blockade by this new renin inhibitor. METHODS AND RESULTS: Twenty-four male volunteers participated in a double-blind randomized, placebo-controlled in-hospital study to evaluate the effects of zankiren HCl (10 to 250 mg). All subjects were pretreated with 40 mg furosemide 12 hours before study drug administration. Blood pressure and heart rate were monitored by an automated oscillometric device, and blood samples were obtained for active renin, total renin, plasma renin activity, angiotensin I (Ang I), Ang II, aldosterone, and plasma zankiren concentration. Satisfactory absorption of zankiren HCl was demonstrated by the results of plasma drug concentration determinations, and renin inhibitory activity was confirmed by dose-related suppression of plasma renin activity, Ang I, Ang II, and aldosterone and increases in plasma active renin concentration. Furthermore, hypotensive activity was readily observed in these normotensive subjects, as evidenced by statistically significant dose-related blood pressure reductions (P < .01). CONCLUSIONS: Results from this study demonstrate for the first time that oral administration of a renin inhibitor can dose-dependently decrease blood pressure and circulating components of the RAS in normotensive volunteers as a result of documented absorption.

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a renin inhibitor). II: A dose-ranging study in patients with congestive heart failure.

This study describes the relationship between the measured effects (the acute effects on systemic hemodynamics and cardiac function) and plasma drug levels using a combined pharmacokinetic-pharmacodynamic model after i.v. infusion dosing of enalkiren (A-64662) in patients with congestive heart failure. Ascending doses from 0.003 to 1.0 mg/kg were evaluated. Timed blood samples were obtained to measure enalkiren levels in plasma. The plasma level-effect plots showed little or no hysteresis. A sigmoid Emax model was used to develop the relationship between the predicted plasma enalkiren levels and hemodynamic effects. Although hemodynamic effects were observed for most patients, random noise in the dynamics or modest net effects compared to baseline fluctuations precluded simultaneous modeling of the pharmacokinetics and pharmacodynamics for a few patients. While the sensitivity toward enalkiren's effects varied substantially among this group of patients, the studywide estimates of the EC50 for the blood pressure measures averaged about 3,500 ng/ml. The mean EC50 for systolic blood pressure (SBP, 2,744 ng/ml) was lower than those of diastolic blood pressure (DBP, 3,438 ng/ml) and mean arterial pressure (MAP, 3,371 ng/ml), suggesting that the SBP might be a more sensitive measure than the other two.

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a new renin inhibitor). I: Single dose study.

This study describes the relationship between the measured effects (angiotensin I and renal plasma flow) and plasma drug levels using a combined pharmacokinetic-pharmacodynamic model after 90 min iv infusion of enalkiren in 15 healthy, salt-depleted subjects. Doses from 0.002 to 0.512 mg/kg were evaluated. One hour prior to enalkiren dosing, para-aminohippuric acid infusion was started for each subject and continued until 3 hr after the start of enalkiren infusion. Timed blood samples were obtained to measure enalkiren, para-aminohippuric acid, and angiotensin I levels in plasma. Enalkiren-induced effect changes lagged in time behind the plasma enalkiren level changes, showing a counterclockwise hysteresis loop. To relate the temporal relationship of effect changes accurately to plasma drug levels, a pharmacokinetic model was combined with a pharmacokinetic model that incorporated a hypothetical effect compartment. The magnitude of the time lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma enalkiren levels (t1/2keo). The t1/2keo for angiotensin I (0.002 hr) is significantly shorter than that of renal plasma flow (0.267 hr), indicating that enalkiren equilibrates more rapidly with the angiotensin I-related effect compartment than the renal plasma flow-related effect compartment. Moreover, the model allows for estimation of the effect site concentration that causes one-half of the maximal predicted effect (EC50), which is a measure of an individual's sensitivity to enalkiren. The EC50 of angiotensin I (81.1 ng/ml) is substantially lower than that of renal plasma flow (4414 ng/ml), indicating that angiotensin I may be a more sensitive measure of enalkiren effects than renal plasma flow.

Renin inhibitors in hypertension.

The renin-angiotensin system (RAS) is an important modulator of blood pressure and fluid balance. The clinical success of angiotensin converting enzyme inhibitors (ACEIs) in the treatment of hypertension has stimulated the search for antagonists of renin. Because renin is highly specific for its substrate, angiotensinogen, renin inhibitors may emerge as clinically preferable alternatives to ACEIs, which affect multiple biological systems, including bradykinin and prostaglandin metabolism. Recent advances in renin inhibitor chemistry have produced highly specific and potent, transition-state analogs of angiotensinogen. Several compounds (e.g., enalkiren, ditekiren, CGP 38560A, and RO 42-5892) have been tested in man. These renin inhibitors produce dose-dependent decreases in plasma renin activity (PRA) which are dissociated from the dose-dependent decreases in blood pressure (BP). Potential explanations for this dissociation include methodologic errors in PRA assays and alternate sites or mechanisms of drug action, including inhibition of noncirculating tissue renin. A prolonged hypotensive effect is seen following single doses of enalkiren and RO 42-5892, and repeated dosing with enalkiren results in sustained hypotensive effect without tachyphylaxis. Renin inhibitors can reduce blood pressure irrespective of baseline renin status and sodium balance. However, high-renin patients generally respond more vigorously, and the hypotensive response is enhanced by sodium depletion. In general, renin inhibitors have been safe and well tolerated in limited clinical studies. New generation renin inhibitors with higher potency and greater oral bioavailability may join the antihypertensive armamentarium.

Immediate blood pressure effects of the renin inhibitor enalkiren and the angiotensin-converting enzyme inhibitor enalaprilat.

The antihypertensive effects of the renin inhibitor enalkiren were compared with those of the angiotensin-converting enzyme inhibitor enalaprilat in 17 hypertensive patients (14 white, 3 black; mean age 57 years), whose renin systems had been stimulated by diuretic pretreatment. Patients were studied on 3 separate in-hospital days. On the first study day patients received placebo alone. On day 2 they received intravenous bolus doses of enalkiren (0.03 to 1.0 mg/kg), and on day 3, intravenous bolus doses of enalaprilat (0.625 to 1.25 mg). Each agent reduced systolic (p less than 0.01) and diastolic (p less than 0.01) blood pressure (BP) from baseline levels. The acute decrease in systolic BP of 18.5 +/- 0.4 mm Hg during enalkiren tended to be greater (p less than 0.01) than the decrease of 12.6 +/- 0.7 mm Hg during enalaprilat. Decreases in diastolic BP during enalkiren (11.9 +/- 0.4 mm Hg) were also slightly greater (p less than 0.1) than those during enalaprilat (9.2 +/- 0.4 mm Hg). Based on prestudy plasma renin activity (PRA), patients were divided into "high" renin (PRA greater than 3.5 ng angiotensin l/ml/hr; n = 6) and "low/normal" renin (less than 3.5 ng angiotensin l/ml/hr; n = 11) groups. Reductions in diastolic BP in the "high" renin group during enalkiren (30 +/- 5/20 +/- 3 mm Hg) tended to be greater (p less than 0.07) than those during enalaprilat (23 +/- 7/14 +/- 1 mm Hg); differences were not significant in the "low/normal" group (12 +/- 2/7 +/- 2 and 7 +/- 2/8 +/- 1 mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of renin inhibition in systemic hypertension.

The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet, plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for greater than or equal to 6 hours (11.9 +/- 4 to 1.0 +/- 0.6 ng angiotensin I/ml/hour, p less than 0.05). Mean arterial blood pressure declined gradually (108 +/- 5 to 84 +/- 4 mm Hg, p = 0.02), as did plasma aldosterone concentration (14.4 +/- 3.8 to 4.4 +/- 0.8 ng/dl, p = 0.03), whereas plasma immunoreactive active renin concentration increased progressively (35 +/- 14 to 160 +/- 60 pg/ml, p greater than 0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin F1 alpha) decreased slightly, but not significantly (42 +/- 10 to 33 +/- 11 ng/g creatinine, p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system, without significantly altering urinary prostacyclin excretion, in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension.

Prolonged duration of blood pressure response to enalkiren, the novel dipeptide renin inhibitor, in essential hypertension.

The effects of sustained renin inhibition by repeated administration of enalkiren (A-64662), the novel dipeptide renin inhibitor, were evaluated in a randomized, double-blind, placebo-controlled, parallel-group study of 32 inpatients (eight per group) with essential hypertension who were maintained on a diet containing 60 meq/day sodium. Three different dosage regimens of enalkiren were studied: 1) 1.2 mg/kg quotid., 2) 0.3 mg/kg q.i.d., and 3) 0.1 mg/kg q.i.d. Each patient received an intravenous infusion every 6 hours for 1 week. Placebo infusions were used to mimic the 4 times/day dosing schedule. Blood pressure was measured periodically via 24-hour automated monitoring equipment. Mean plasma renin activity in the patient groups ranged from 1.58 to 2.68 ng angiotensin I/ml/hr. Plasma renin activity was promptly suppressed in all groups receiving enalkiren. Prolonged duration of plasma renin activity suppression (greater than or equal to 24 hours) was demonstrated after the administration of 1.2 mg/kg enalkiren. The 0.3 mg/kg q.i.d. and 1.2 mg/kg quotid. regimens produced statistically significant reductions (p less than or equal to 0.05) in systolic and diastolic blood pressures with clear evidence of persistent antihypertensive activity for 12 hours or more when compared with the placebo group. Despite relatively large reductions in mean systolic and diastolic blood pressure, mean pulse rates were essentially unchanged. The prolonged reduction in blood pressure with enalkiren without evidence of tachyphylaxis after 1 week of treatment suggests that renin inhibitors may emerge as useful therapeutic agents for the treatment of hypertension.

Assessment of renin dependency of hypertension with a dipeptide renin inhibitor.

To evaluate the participation of the renin-angiotensin system in sustaining hypertension, we administered the specific dipeptide renin inhibitor enalkiren (A-64662) to 18 patients with essential hypertension. Ascending intravenous bolus doses (0.03, 0.1, 0.3, and 1.0 mg/kg) of the inhibitor were each given at 45-minute intervals to patients maintained on an ad libitum sodium diet who were studied while in bed in the semirecumbent posture. Enalkiren produced marked decreases in plasma renin activity (PRA) that were still evident 8 hours after completion of dosing. Systolic and diastolic blood pressures were decreased in a dose-dependent fashion without an effect on heart rate. Repetition of this procedure after patients were subjected to sodium depletion by 1 week of thiazide treatment produced amplified decreases in blood pressure. Despite the short plasma half-life of the inhibitor, these blood pressure-lowering effects were sustained for 4-8 hours when compared with parallel placebo administration in the same patients. Both the baseline PRA and the inhibitor-induced changes in PRA correlated significantly with blood pressure changes during the unstimulated and the sodium-depleted studies. However, effects of the inhibitor on diastolic blood pressure in the latter study correlated most closely with actual increases in renin produced by diuretic pretreatment. Thus, this specific renin inhibitor has demonstrated the dependency of blood pressure on the renin-angiotensin system even during basal conditions in hypertensive patients. Moreover, renin response to sodium depletion appears to be an attribute that additionally characterizes individual hypertensive patients.

Clinical pharmacology of enalkiren, a novel, dipeptide renin inhibitor.

Enalkiren (A-64662), a potent, dipeptide renin inhibitor, mimics the transition state of the human renin substrate, angiotensinogen. Enalkiren has been shown to produce dose-related suppression of plasma renin activity (PRA) and angiotensin II when administered intravenously. Doses of enalkiren of less than 0.1 mg/kg induced little hemodynamic response in normotensive and hypertensive volunteers despite marked suppression of PRA. However, at doses of 0.3 and 1.2 mg/kg, enalkiren produced significant, dose-related decreases in systolic and diastolic blood pressure (BP) in hypertensive patients, and the BP response was enhanced by pretreatment with hydrochlorothiazide. The effects of enalkiren on PRA and BP are prolonged despite its relatively short elimination phase plasma half-life (1.6 h). Persistent pharmacologic activity without evidence of tachyphylaxis was demonstrated during 1 week of treatment in hypertensive patients. The observed dissociation between suppression of PRA and BP response and the recruitment of dose-related BP decrements, despite complete suppression of PRA, are unexplained phenomena. The results of clinical trials with enalkiren are encouraging, and suggest that renin inhibitors may be safe, useful therapeutic agents in the management of hypertension.