Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects.

OBJECTIVE: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). METHODS: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). RESULTS: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. CONCLUSIONS: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.

Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil.

OBJECTIVE: Ezetimibe is a novel lipid-lowering drug that prevents intestinal absorption of dietary and biliary cholesterol leading to significant reduction in total-C, LDL-C, Apo B, and TG and increases in HDL-C in patients with hypercholesterolemia. Gemfibrozil, a fibric acid derivative, is an effective lipid-modulating agent that increases serum high-density lipoprotein cholesterol and decreases serum TG. The objective of this study was to evaluate the potential for a pharmacokinetic (PK) interaction between ezetimibe and gemfibrozil. METHODS: This was a randomized, open-label, 3-way crossover, multiple-dose study in 12 healthy adult male volunteers. All subjects received the following 3 treatments orally for 7 days: ezetimibe 10 mg once daily, gemfibrozil 600 mg every 12 hours, and ezetimibe 10 mg once daily plus gemfibrozil 600 mg every 12 hours. A washout period of > or = 7 days separated the 3 treatments. In each treatment, blood samples were collected on day 7 to assess the steady-state PK of ezetimibe and gemfibrozil. The oral bioavailability of ezetimibe coadministered with gemfibrozil relative to each drug administered alone was evaluated with an analysis-of-variance model. RESULTS: Ezetimibe was rapidly absorbed and extensively conjugated to its glucuronide metabolite. Ezetimibe did not alter the bioavailability (based on AUC) of gemfibrozil. The mean AUC0-12 of gemfibrozil was 74.7 and 74.1 microg h/ml with and without ezetimibe coadministration, respectively (log-transformed geometric mean ratio (GMR) = 99.2; 90% confidence interval (CI) = 92 - 107%). Conversely, gemfibrozil significantly (p < 0.05) increased the plasma concentrations of ezetimibe and total ezetimibe (i.e. ezetimibe plus ezetimibe-glucuronide). Exposure to ezetimibe and total ezetimibe was increased approximately 1.4-fold and 1.7-fold, respectively (CI = 109 - 173% for ezetimibe and 142 - 190% for total ezetimibe), however, this increase was not considered to be clinically relevant. Ezetimibe and gemfibrozil administered alone or concomitantly for 7 days was well tolerated. CONCLUSIONS: The coadministration of ezetimibe and gemfibrozil in patients is unlikely to cause a clinically significant drug interaction. The coadministration of these agents is a promising approach for patients with mixed dyslipidemia. Additional clinical studies are warranted.

The plasma concentration and LDL-C relationship in patients receiving ezetimibe.

Ezetimibe is a novel selective inhibitor of intestinal cholesterol absorption, which has been shown to significantly decrease low-density lipoprotein cholesterol (LDL-C). In this article, the relationship between plasma ezetimibe concentrations and lowering of LDL-C is determined using Emax and regression models. Data from two phase II double-blind placebo-controlled studies (n = 232 and 177) were used in which daily doses of ezetimibe ranging from 0.25 to 10 mg were administered for 12 weeks. Ezetimibe concentrations correlated significantly with percentage change in LDL-C from baseline (%LDL-C). Reductions in %LDL-C of 10%, 15%, and 20% were achieved with concentrations in the ranges 0 to 2, 2 to 15, and > 15 ng/ml, respectively, as compared with placebo. To achieve > 15% reduction in LDL-C, patients need to maintain trough concentrations > 15 ng/ml, taking plasma concentrations as a surrogate for concentrations at the enterocyte. Based on the doses administered, the 10 mg dose had the highest likelihood of sustaining such concentrations, confirming that a daily 10 mg dose of ezetimibe is an optimal therapeutic dose in the treatment of hypercholesterolemia.

A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe.

BACKGROUND: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, is in clinical development for the treatment of hypercholesterolemia. It is rapidly absorbed and glucuronidated in the intestine. The parent compound and its conjugated metabolite undergo enterohepatic recirculation, resulting in multiple peaks in the plasma concentration-time profile. OBJECTIVE: The purpose of this study was to develop a population pharmacokinetic (PPK) model for ezetimibe that incorporates enterohepatic recirculation. METHODS: A population compartment model incorporating input from the gallbladder, consistent with food intake, was developed to account for enterohepatic recirculation. The amount recycled was allowed to vary within a subject and between subjects, accommodating variability in bile secretion. The data used consisted of 90 profiles from healthy subjects who received single or multiple doses of ezetimibe 10 or 20 mg. Modeling was carried out using a nonlinear mixed-effect function in the S-PLUS statistical program. RESULTS: The amount of ezetimibe recycled into the central compartment was estimated to be approximately 17% to 20% of the total amount absorbed, independent of the volume of distribution. The intersubject coefficient of variation was 46% to 80% in the absorption rate constant, 27% in the distribution phase, and approximately 50% in the volume of distribution. CONCLUSIONS: PPK models adapted for enterohepatic recirculation allowed a formal assessment of the magnitude and frequency of the enterohepatic recirculation process, and the associated intersubject and intrasubject variability in healthy subjects. The PPK approach also helped to assess the correlation between the observed maximum or minimum (24 hours postdose) concentration with the model-based area under the curve, confirming the appropriateness of the former measures as a surrogate of drug exposure for a possible correlation with pharmacodynamics.

Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention.

BACKGROUND: Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. METHODS AND RESULTS: Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later. CONCLUSIONS: A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.

Mometasone furoate has minimal effects on the hypothalamic-pituitary-adrenal axis when delivered at high doses.

STUDY OBJECTIVES: To investigate the potential for mometasone furoate (MF) to exert systemic effects following administration by dry powder inhaler (DPI) or metered-dose inhaler (MDI). DESIGN: Three randomized, evaluator-blind, placebo-controlled, parallel-group, 28-day studies. PATIENTS: Adults with mild-to-moderate persistent asthma. INTERVENTIONS: Study 1 (12 patients per treatment group; MF DPI at 200 microg bid, 400 microg qd, 800 microg qd, or 1,200 microg qd). Study 2 (16 patients per treatment group; MF DPI at 400 microg bid or 800 microg bid, or oral prednisone at 10 mg qd). Study 3 (16 patients per treatment group; MF MDI at 400 microg bid or 800 microg bid, or fluticasone propionate [FP] at 880 microg bid by MDI). MEASUREMENTS AND RESULTS: Study 1. Plasma concentrations were near the lower limit of quantitation (50 pg/mL) at the MF DPI 400-microg qd dosage and approximately 250 pg/mL at the 1,200-microg qd dosage. The area under the curve for serum cortisol concentrations over 24 h (AUC(24)) was essentially unaltered at all doses. Study 2. Plasma levels over days 7 to 28 were 100.3 +/- 5.9 pg/mL (mean +/- SEM) for MF DPI 400 microg bid, and 181.0 +/- 10.9 pg/mL for 800 microg bid. Although there were relatively low levels of suppression (19 to 25%) at earlier time points for MF DPI 400 microg bid, serum cortisol AUC(24) levels at day 28 were similar to placebo. MF DPI 800 microg bid and oral prednisone both decreased serum cortisol AUC(24) levels at days 7 to 28 by 28.0 +/- 8.3% and 67.2 +/- 3.6%, respectively. The response to cosyntropin was normal in 15, 14, 11, and 1 of the patients in the placebo, MF DPI 400 microg bid, MF DPI 800 microg bid, and prednisone groups, respectively. Study 3. MF MDI caused even less systemic exposure than by DPI. MF MDI 800 microg bid (24.0 +/- 3.1%) and FP (51.7 +/- 3.8%) caused a significant decrease in serum cortisol AUC(24) on days 14 to 28. MF MDI 400 microg bid was similar to placebo treatment at all time points. CONCLUSIONS: The MF 800-microg bid dosage (1,600 microg/d), which is twice the highest projected clinical dosage, represents the lower limit for consistently detectable systemic effects of MF.

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine.

AIMS: To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. METHODS: Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. RESULTS: Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. CONCLUSIONS: Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.

Disposition of 14C-eptifibatide after intravenous administration to healthy men.

Eptifibatide, a synthetic peptide inhibitor of the platelet glycoprotein IIb/IIIa receptor, has been studied as an antithrombotic agent in a variety of acute ischemic coronary syndromes. The purpose of the present study was to characterize the disposition of 14C-eptifibatide in man after a single intravenous (i.v.) bolus dose. 14C-Eptifibatide (approximately 50 microCi) was administered to eight healthy men as a single 135-microgram/kg i.v. bolus. Blood, breath carbon dioxide, urine, and fecal samples were collected for up to 72 hours postdose and analyzed for radioactivity by liquid scintillation spectrometry. Plasma and urine samples were also assayed by liquid chromatography with mass spectrometry for eptifibatide and deamidated eptifibatide (DE). Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. Plasma eptifibatide concentrations and radioactivity declined in parallel, with most of the radioactivity (82.4%) attributed to eptifibatide. A total of approximately 73% of administered radioactivity was recovered in the 72-hour period following 14C-eptifibatide dosing. The primary route of elimination was urinary (98% of the total recovered radioactivity), whereas fecal (1.5%) and breath (0.8%) excretion was small. Eptifibatide is cleared by both renal and nonrenal mechanisms, with renal clearance accounting for approximately 40% of total body clearance. Within the first 24 hours, the drug is primarily excreted in the urine as unmodified eptifibatide (34%), DE (19%), and more polar metabolites (13%).

Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II.

We examined for the first time the specific roles of angiotensin II and the natriuretic peptides during inhibition of angiotensin-converting enzyme (captopril, 25 mg bolus + 6 mg/3 h infusion) and endopeptidase 24.11 (SCH32615, 5 mg/kg bolus + 3 mg/kg/3 h infusion), both separately and in combination, in eight sheep with pacing-induced heart failure. Plasma atrial and brain natriuretic peptide levels were similarly increased by SCH32615 and to a lesser extent during combined inhibition but decreased with captopril. Captopril and combined inhibition induced identical increases in plasma renin activity and reductions in angiotensin II, whereas neither was changed by SCH32615 alone. Mean arterial pressure and peripheral resistance decreased during SCH32615 and further still during captopril and combined treatment. Left atrial pressure was reduced to a similar extent by SCH32615 and captopril alone and reduced further by combined inhibition. Cardiac output increased during all treatments. Urine volume and sodium excretion were significantly increased during SCH32615 and combined inhibition. Creatinine clearance increased during SCH32615, decreased during captopril, and was maintained during combined treatment. In conclusion, compared with captopril alone, cotreatment with an endopeptidase 24.11 inhibitor further improved filling pressures and induced a diuresis and natriuresis with preservation of renal glomerular filtration.

Clearance receptors and endopeptidase: equal role in natriuretic peptide metabolism in heart failure.

The effects of separate and combined endopeptidase inhibition (by SCH-32615) and natriuretic peptide receptor C blockade [by C-ANP-(4-23)] on the clearance and bioactivity of atrial (ANP) and brain (BNP) natriuretic peptides was investigated in eight sheep with heart failure. SCH-32615 and C-ANP-(4-23) administered separately induced significant and proportionate dose-dependent rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP) levels. Associated with these changes were reductions in arterial pressure, left atrial pressure, and peripheral resistance and increases in cardiac output, urine volume, sodium excretion, and creatinine clearance. SCH-32615 induced greater diuresis and natriuresis than C-ANP-(4-23). Combined administration of SCH-32615 and C-ANP-(4-23) induced greater than additive rises in plasma ANP, BNP, and cGMP concentrations, with enhanced hemodynamic effects, diuresis, and natriuresis and reduced plasma aldosterone levels. In conclusion, we find that the enzymatic and receptor clearance pathways contribute equally to the metabolism of endogenous ANP and BNP in sheep with heart failure. Combined inhibition of both degradative pathways was associated with enhanced hormonal, hemodynamic, and renal effects and may have greater potential therapeutic value than either agent separately.

Pharmacokinetics of loratadine and pseudoephedrine following single and multiple doses of once- versus twice-daily combination tablet formulations in healthy adult males.

The pharmacokinetic profiles of single and multiple doses of loratadine, descarboethoxyloratadine (DCL) (the major active metabolite of loratadine), and pseudoephedrine were determined in a randomized, open-label, two-way crossover study in 24 healthy men. Subjects received a single dose (day 1) and multiple doses (days 3 to 10) of a once-daily (QD) formulation of loratadine 10 mg in an immediate-release coating and pseudoephedrine sulfate 240 mg in an extended-release core (CLAR-ITIN-D 24 HOUR tablets), and a twice-daily (BID) formulation of loratadine 5 mg in an immediate-release coating and pseudoephedrine sulfate 120 mg, with 60 mg in an immediate-release coating and 60 mg in the barrier-protected core (CLARITIN-D 12 HOUR tablets) in study sessions, each separated by a 10-day washout period. Both regimens were safe and well tolerated. On day 1, plasma loratadine, DCL, and pseudoephedrine concentrations were higher following the QD formulation than following the BID formulation, as expected. On day 10, loratadine and DCL maximum plasma concentration (Cmax) values were, on average, 87% and 35% higher, respectively, for the QD formulation than for the BID formulation; however, the values of the area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) for loratadine and DCL were equivalent (90% confidence interval [CI]: 83% to 110% for loratadine; 90% to 107% for DCL). On day 10, pseudoephedrine Cmax and AUC0-24 values were equivalent (90% CI for Cmax: 94% to 109%; for AUC: 91% to 106%) for the two formulations, and lower pseudoephedrine concentrations were observed from 16 to 24 hours with the QD formulation. Both loratadine/pseudoephedrine formulations produced equivalent loratadine and DCL AUC0-24 values and equivalent pseudoephedrine Cmax and AUC0-24 values following multiple dosing. The lower pseudoephedrine concentrations in the evening with the QD formulation may minimize the potential for insomnia in patients when compared with the BID formulation.

Influence of food on the oral bioavailability of loratadine and pseudoephedrine from extended-release tablets in healthy volunteers.

The effect of a high-fat breakfast on the bioavailability of the components of an extended-release tablet containing 10 mg loratadine in the immediate-release coating and 240 mg pseudoephedrine sulfate in the extended-release core was studied in 24 healthy male volunteers in a single-dose, two-way crossover study. The drug was administered after a 10-hour overnight fast or within 5 minutes of consuming a standardized high-fat breakfast. Serial blood samples were collected over a 48-hour period, and plasma was analyzed for loratadine and its active metabolite descarboethoxyloratadine (DCL), and pseudoephedrine. For pseudoephedrine, maximum concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUCzero-infinity) were similar after both treatments, indicating no relevant food effect on the bioavailability of pseudoephedrine. Also, the absorption profiles of pseudoephedrine (from Wagner-Nelson analysis) were similar for the fed and fasted treatments, indicating no apparent differences in absorption. Plasma concentration-time profiles and values for Cmax and AUCzero-infinity of DCL were similar for the two treatments, indicating no relevant food effect on the pharmacokinetics of DCL. In contrast, for loratadine, administration with food resulted in a significantly increased mean Cmax (53%) and AUC from time zero to the final quantifiable sample (AUCif) (76%). However, the resultant Cmax and AUC of loratadine under fed conditions were well below those previously obtained at steady-state after multiple-dose administration of loratadine (40 mg/day) that were shown to be safe and well-tolerated in several clinical studies. The effect of food on the bioavailability and pharmacokinetic profiles of the components of a combination loratadine/pseudoephedrine extended-release tablet is not likely to be clinically significant.

Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure.

1. Atrial and brain natriuretic peptide are both circulating hormones subject to degradation by neutral endopeptidase 24.11. Whereas endogenous levels of atrial natriuretic peptide are increased by neutral endopeptidase inhibition in most pathophysiological states, the effect on brain natriuretic peptide and the influence of cardiac status is less clear. To further evaluate the role of neutral endopeptidase 24.11, we directly compared the responses of atrial and brain natriuretic peptide, together with the effects on other vasoactive hormones, haemodynamics and renal indices, to a neutral endopeptidase inhibitor, SCH32615, and a vehicle control in eight conscious sheep before and during pacing-induced heart failure. 2. In normal animals, SCH32615 significantly increased concentrations of plasma atrial natriuretic peptide (22 +/- 5 pmol/l compared with 14 +/- 2 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (6.5 +/- 1.2 pmol/l compared with 4.1 +/- 0.7 pmol/l in control, 1.6-fold increase), whereas in heart failure, plasma levels of atrial natriuretic peptide (306 +/- 38 pmol/l compared with 187 +/- 25 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (93 +/- 11 pmol/l compared with 55 +/- 9 pmol/l in control, 1.7-fold increase) were elevated to a significantly greater absolute, but proportionately similar, extent. In both normal and heart-failed animals, SCH32615 induced reductions in mean arterial pressure and left atrial pressure and increases in haematocrit, plasma cGMP and endogenous creatinine clearance. However, only in heart failure did neutral endopeptidase inhibition induce a significant and marked natriuresis (> 10-fold increase) and diuresis (4-fold increase), together with suppression of renin activity and haemodynamic effects including decreased peripheral resistance and raised cardiac output. 3. In conclusion, neutral endopeptidase inhibition increases plasma concentrations of atrial and brain natriuretic peptide to a proportionately similar extent in both normal and heart-failed sheep. The striking natriuresis and diuresis and additional haemodynamic effects demonstrated in sheep with heart failure, where natriuretic peptide levels are elevated compared with normal sheep, supports the concept that neutral endopeptidase inhibition augments endogenous atrial and brain natriuretic peptide.

Clearance receptors and endopeptidase 24.11: equal role in natriuretic peptide metabolism in conscious sheep.

Although many studies have examined the effects of administering natriuretic peptide receptor C (NPR-C) ligands and endopeptidase 24.11 (EP 24.11) inhibitors on clearance and bioactivity of atrial natriuretic peptide (ANP), none have systematically compared their effects on the endogenous levels of both ANP and brain natriuretic peptide (BNP) under physiological conditions. Accordingly, we examined the hemodynamic, hormonal, and renal actions of an EP 24.11 inhibitor, SCH-32615, and an NPR-C ligand, C-ANP-(4-23), both alone and in combination in eight normal conscious sheep. NPR-C blockade and EP 24.11 inhibition induce similar rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP). Synergistic increments in plasma ANP, BNP, and cGMP observed during combined administration are likely to be due to the reduced clearance of C-ANP-(4-23) in the setting of EP 24.11 inhibition, leading to increased inhibition of the receptor pathway. Combined administration was also associated with enhanced hemodynamic actions and diuretic and natriuretic effects. Our findings show that both enzymatic and receptor clearance pathways contribute equally to natriuretic peptide clearance and induce potentially important hemodynamic and renal effects in normal conscious sheep.

Pharmacokinetics of isosorbide-5-mononitrate after oral administration of an extended-release mononitrate formulation versus a standard dinitrate formulation.

The steady-state pharmacokinetic profile of isosorbide-5-mononitrate (5-ISMN) after oral administration of an extended-release tablet formulation of 5-ISMN 60 mg or 120 mg once a day was compared with that after administration of isosorbide dinitrate (ISDN) 40 mg every 6 hours, in a randomized, open-label, three-way crossover trial in 24 healthy men. After oral administration of extended-release 5-ISMN 60 mg or 120 mg once daily, 5-ISMN was slowly absorbed, reaching mean peak plasma concentrations of 557 and 1151 ng/mL, respectively, in approximately 3 hours. Plasma concentrations of 5-ISMN were dose proportional between 60 mg and 120 mg. After oral administration of ISDN 40 mg every 6 hours, a mean peak plasma 5-ISMN concentration of 806 ng/mL was achieved in less than 2 hours (mean time to reach the maximum plasma concentration was 1.5 hours). The mean plasma apparent elimination half-life of 5-ISMN was 6.2 hours after extended-release 5-ISMN administration and 7.1 hours after ISDN. Although the maximum plasma concentration was higher and the minimum plasma concentration was lower after administration of extended-release 5-ISMN 120 mg once daily compared with ISDN 40 mg every 6 hours, there was no significant difference (P > 0.05) in the "bioavailability" of 5-ISMN between these two treatments. The most commonly reported adverse events in these "nitrate-naive" subjects were headache, dizziness, nausea, and vomiting; these were dose related and their incidence decreased with repeated exposure.

Effect of food on the oral bioavailability of isosorbide-5-mononitrate administered as an extended-release tablet.

We evaluated the effect of a high-fat breakfast and gastric emptying rate on the oral bioavailability of a isosoribide-5-mononitrate (5-ISMN) controlled-release tablet formulation (IMDUR 60-mg tablets, Astra Hässle AB, Mölndal, Sweden) relative to an oral solution in 18 healthy men. Gastric emptying was monitored by radiotelemetry using the Heidelberg capsule technique. After administration of the 5-ISMN 60-mg solution, absorption was rapid with mean peak plasma 5-ISMN concentrations of 1533 ng/mL achieved in less than 1 hour. In contrast, after administration of IMDUR 60-mg tablets, the drug was more slowly absorbed, reaching mean peak plasma concentrations of 541 ng/mL in 3 to 4 hours. The bioavailability of 5-ISMN from IMDUR tablets under fasted conditions was approximately 78% relative to the solution; and, in the presence of food, the bioavailability was slightly increased to 86% (P = .057). The mean gastric residence time of IMDUR tablets under fasted conditions was 68 minutes, and in the presence of food was increased to 478 minutes, with 9 of the 18 subjects having gastric emptying delayed for at least 600 minutes. We conclude that in the presence of food, gastric emptying time is considerably increased causing a delay in drug absorption and a slight increase in the bioavailability of 5-ISMN from this controlled-release tablet formulation, however this effect is not clinically relevant.

Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension.

SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the ¿link¿ model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid Emax PD model. For the 300 mg BID dose, PD parameters were: maximum effect (Emax), 8.1 mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC50), 0.87 microgram x ml(-1); and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple Emax PD model. PD parameters obtained over the dose range were: Emax, 10.3 mmHg; Eo, 2.0 mmHg; and EC50 0.7 microgram x ml(-1). These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 microgram x ml(-1).

Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute inhibition of endopeptidase 24.11 in essential hypertension: SCH 34826 enhances atrial natriuretic peptide and natriuresis without lowering blood pressure.

The acute renal, endocrine, and hemodynamic effects of the orally active endopeptidase inhibitor SCH 34826 (400 mg every 6 hours for five doses) were investigated in a group of 6 male patients [with established mild to moderate essential hypertension and left ventricular (LV) hypertrophy] in a balanced random-order double-blind, placebo-controlled cross-over study. Plasma atrial natriuretic factor (ANF) concentrations increased (p < 0.05) to fourfold control values after the first dose of inhibitor, but later postdose increments of ANF were less pronounced. Plasma cyclic GMP also increased significantly (p < 0.05). These effects were associated with a transient modest but significant (p < 0.05) increase in sodium excretion (50 mmol sodium in excess of placebo values) that was complete in 24 h. Mean 24-h urinary excretions of cyclic GMP and immunoreactive ANF were also significantly increased by 55 and 86%, respectively. Other urine indexes (including other electrolytes, volume, creatinine, aldosterone, and cortisol) and renal hemodynamics [including glomerular filtration rate (GFR) and effective renal plasma flow (RPF)] were unchanged. Renin-angiotensin-aldosterone system (RAAS) activity was not significantly altered. Plasma epinephrine increased after the initial three doses of SCH 34826. Systolic blood pressure (SBP) and heart rate (HR) were not altered by SCH 34826. Diastolic BP (DBP) increased slightly (p = 0.044). Acute inhibition of endopeptidase 24.11 by SCH 34826 in essential hypertension caused significant increments in plasma ANF and cyclic GMP together with modest natriuresis. No antihypertensive effect was observed in the first 30 h of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of SCH 34826, an orally active inhibitor of atrial natriuretic peptide degradation, in healthy volunteers.

Atrial natriuretic peptide is cleared from plasma by clearance receptors and by enzymatic degradation by way of a neutral metalloendopeptidase. Inhibition of neutral metalloendopeptidase activity appears to provide an interesting approach to interfere with metabolism of atrial natriuretic peptide to enhance the renal and haemodynamic effects of endogenous atrial natriuretic peptide. In this study, the effects of SCH 34826, a new orally active neutral metalloendopeptidase inhibitor, have been evaluated in a single-blind, placebo-controlled study involving eight healthy volunteers who had maintained a high sodium intake for 5 days. SCH 34826 had no effect on blood pressure or heart rate in these normotensive subjects. SCH 34826 promoted significant increases in excretion of urinary sodium, phosphate, and calcium. The cumulative 5-hour urinary sodium excretion was 15.7 +/- 7.3 mmol for the placebo and 22.9 +/- 5, 26.7 +/- 6 (p less than 0.05), and 30.9 +/- 6.8 mmol (p less than 0.01) for the 400, 800, and 1600 mg SCH 34826 doses, respectively. During the same time interval, the cumulative urinary phosphate excretion increased by 0.3 +/- 0.4 mmol after placebo and by 1.5 +/- 0.3 (p less than 0.01), 1.95 +/- 0.3 (p less than 0.01), and 2.4 +/- 0.4 mmol (p less than 0.001) after 400, 800, and 1600 mg SCH 34826, respectively. There was no change in diuresis or excretion of urinary potassium and uric acid. The natriuretic response to SCH 34826 occurred in the absence of any change in plasma atrial natriuretic peptide levels but was associated with a dose-dependent elevation of urinary atrial natriuretic peptide and cyclic guanosine monophosphate.(ABSTRACT TRUNCATED AT 250 WORDS)