Acceptability of multiple coated mini-tablets in comparison to syrup in infants and toddlers: a randomised controlled study.

OBJECTIVES: Drug treatment of children is often limited to liquid formulations or manipulation of adult solid oral dosage forms because of the lack of age-appropriate formulations, concerns around particle aspiration and paediatric acceptability. Recent research revealed that the administration of mini-tablets has substantial advantages in improving dose accuracy and avoiding issues related to drug stability, storage conditions, potentially toxic excipients and taste masking (especially effective when the mini-tablets are coated). Most trials were performed with single and multiple uncoated mini-tablets. This study here aimed to investigate young children's acceptability and swallowability of multiple coated placebo mini-tablets compared with glucose syrup. DESIGN: This clinical trial was conducted as a single-centre randomised cross-over study. SETTING: Prospective cross-over study performed at the Children's University Hospital Düsseldorf. PATIENTS: This study was conducted on 50 children in five age groups from 1 to <6 years. INTERVENTIONS: An age-adapted amount of 16-28 mini-tablets and 3-6 mL syrup was administered in randomised order. MAIN OUTCOME MEASURES: Acceptability and swallowability of multiple coated mini-tablets and syrup. RESULTS: In all age groups, administration of multiple coated mini-tablets and syrup showed good acceptability (mini-tablets 80%-100%, syrup 90%-100%) and swallowability (mini-tablets 30%-70%, syrup 20%-80%) without any clinically meaningful difference. This is consistent with results from large studies with uncoated mini-tablets. CONCLUSION: Multiple coated mini-tablets are a suitable age-appropriate alternative to liquid formulations in the paediatric population. No safety concerns with the use of coated mini-tablets were observed in the study. TRIAL REGISTRATION NUMBER: DRKS00010395.

Clinical Investigation of Metabolic and Renal Clearance Pathways Contributing to the Elimination of Fevipiprant Using Probenecid as Perpetrator.

Fevipiprant, an oral, nonsteroidal, highly selective, reversible, and competitive prostaglandin D2 receptor 2 antagonist, is eliminated by glucuronidation and by direct renal excretion predominantly via organic anion transporter (OAT) 3. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and OAT3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite to support the dosing recommendation of fevipiprant in the presence of drugs inhibiting these pathways; however, phase III clinical trial results did not support its submission. This was a single-center, open-label, single-sequence, two-period crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentrations of fevipiprant increased approximately 1.7-fold, and the area under the concentration-time curve in plasma increased approximately 2.5-fold, whereas the mean apparent volume of distribution and the AG metabolite:fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using these data and those from previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was estimated. Furthermore, a general disposition scheme for fevipiprant was developed, showing how a perpetrator drug such as probenecid, which interferes with two key elimination pathways of fevipiprant, causes only a moderate increase in exposure and allows estimation of the drug-drug inhibition when only one of the two pathways is inhibited. SIGNIFICANCE STATEMENT: In this drug-drug interaction (DDI) study, probenecid was used as a tool to inhibit both glucuronidation and active renal secretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is weak-to-moderate even if a perpetrator drug inhibits several elimination pathways.

On the optimal temporal resolution for phase contrast cardiovascular magnetic resonance imaging: establishment of baseline values.

BACKGROUND: The aim of this study is to quantify the frequency content of the blood velocity waveform in different body regions by means of phase contrast (PC) cardiovascular magnetic resonance (CMR) and Doppler ultrasound. The highest frequency component of the spectrum is inversely proportional to the ideal temporal resolution to be used for the acquisition of flow-sensitive imaging (Shannon-Nyquist theorem). METHODS: Ten healthy subjects (median age 33y, range 24-40) were scanned with a high-temporal-resolution PC-CMR and with Doppler ultrasound on three body regions (carotid arteries, aorta and femoral arteries). Furthermore, 111 patients (median age 61y) with mild to moderate arterial hypertension and 58 patients with aortic aregurgitation, atrial septal defect, or repaired tetralogy of Fallot underwent aortic CMR scanning. The frequency power distribution was calculated for each location and the maximum frequency component, fmax, was extracted and expected limits for the general population were inferred. RESULTS: In the healthy subject cohort, significantly different fmax values were found across the different body locations, but they were nonsignificant across modalities. No significant correlation was found with heart rate. The measured fmax ranged from 7.7 ± 1.1 Hz in the ascending aorta, up to 12.3 ± 5.1 Hz in the femoral artery (considering PC-CMR data). The calculated upper boundary for the general population ranged from 11.0 Hz to 27.5 Hz, corresponding to optimal temporal resolutions of 45 ms and 18 ms, respectively. The patient cohort exhibited similar values for the frequencies in the aorta, with no correlation between blood pressure and frequency content. CONCLUSIONS: The temporal resolution of PC-CMR acquisitions can be adapted based on the scanned body region and in the adult population, should approach approximately 20 ms in the peripheral arteries and 40 ms in the aorta. TRIAL REGISTRATION: This study presents results from a restrospective analysis of the clinical study NCT01870739 (ClinicalTrials.gov).

Variability of MRI Aortic Stiffness Measurements in a Multicenter Clinical Trial Setting: Intraobserver, Interobserver, and Intracenter Variability of Pulse Wave Velocity and Aortic Strain Measurement.

PURPOSE: To assess intraobserver, interobserver, and scan-rescan variability of MRI aortic stiffness measurements in a multicenter trial setting. MATERIALS AND METHODS: This study was a retrospective analysis of prospectively collected data in a multicenter prospective clinical trial (clinicaltrials.gov ID NCT01870739). Forty-five adult patients (31 men; mean age, 58 years ± 12 [standard deviation]; 15 patients per center; three centers) with arterial hypertension underwent standardized 3-T baseline MRI assessments between June and September 2014. Aortic strain was calculated from maximum and minimum aortic area measurements repeated three times by three readers at three aortic levels on three retrospectively gated axial gradient-echo (GRE) data sets. Pulse wave velocity (PWV) was assessed three times by five readers as Δx/Δt: Δx was measured on a parasagittal GRE image of the aortic arch, and Δt was extracted from ascending and descending aortic velocity curves created on three axial phase-contrast acquisitions. Intraobserver, interobserver, and scan-rescan variability was calculated using percentage coefficient of variation (COV). RESULTS: Aortic strain variability was lowest at the level of the distal descending aorta (DDA) with median COVs of 1.6% for intraobserver variability, 4.0% for interobserver variability, and 10.3% for scan-rescan variability. It was highest at the ascending aorta (AA) with COVs of 3.6% for intraobserver variability, 10.7% for interobserver variability, and 19.8% for scan-rescan variability. Variability of PWV was low: 0.7% for intraobserver variability, 1.5% for interobserver variability, and 8.1% for scan-rescan variability. CONCLUSION: Low variability can be achieved for aortic strain and PWV measurements in a multicenter trial setting using standardized MRI protocols. Although COV was lower when measuring aortic strain at DDA compared with AA, variability was acceptable at both anatomic locations.Supplemental material is available for this article.© RSNA, 2020.

Pharmacodynamic interaction between intravenous nitroglycerin and oral sacubitril/valsartan (LCZ696) in healthy subjects.

PURPOSE: Sacubitril/valsartan (LCZ696) and nitroglycerin share the second messenger cGMP and lower blood pressure. Given the potential for co-administration of both drugs in patients with heart failure, this study was designed to investigate the potential for a pharmacodynamic drug interaction affecting blood pressure. METHODS: In this double-blind, placebo-controlled, randomised, crossover study, 40 healthy subjects received sacubitril/valsartan 200 mg bid (97/103 mg bid) or placebo for 5 days. Two hours after the morning dose of sacubitril/valsartan or placebo on day 5, subjects received intravenous nitroglycerin infusion at increasing doses up to 40 µg/min or placebo. Serial measurements of blood pressure (BP), heart rate, biomarkers and sacubitril/valsartan pharmacokinetics were conducted. RESULTS: Administration of nitroglycerin alone led to a dose- and time-dependent decrease in supine systolic BP (SBP) and diastolic BP (DBP) which was similar when nitroglycerin was co-administered with sacubitril/valsartan. At the highest dose of nitroglycerin, the mean (95% CI) decrease from baseline of SBP/DBP was 19.54 (- 21.99, - 17.09)/12.38 (- 13.85, - 10.92) mmHg for nitroglycerin alone compared to 22.63 (- 25.06, - 20.21)/12.94 (- 14.38, - 11.49) mmHg when co-administered with sacubitril/valsartan. Co-administration of sacubitril/valsartan and nitroglycerin did not result in further plasma cGMP increase compared to sacubitril/valsartan alone. The co-administration of nitroglycerin and sacubitril/valsartan was safe and well tolerated and did not impact the pharmacokinetics of sacubitril/valsartan. CONCLUSIONS: The results from this study demonstrate no pharmacodynamic drug interaction between nitroglycerin and sacubitril/valsartan in healthy subjects, suggesting that no change of dose selection and escalation recommendations or clinical monitoring during nitroglycerin administration is required.

Developing Drugs for Heart Failure With Reduced Ejection Fraction: What Have We Learned From Clinical Trials?

There remains a large unmet need for new therapies in the treatment of heart failure with reduced ejection fraction (HFrEF). In the early drug development phase, the therapeutic potential of a drug is not yet fully understood and trial endpoints other than mortality are needed to guide drug development decisions. While a true surrogate marker for mortality in heart failure (HF) remains elusive, the successes and failures of previous trials can reveal markers that support clinical Go/NoGo decisions.

Effect of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of a single dose of furosemide.

AIMS: Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two-period, single-sequence study in healthy subjects. METHODS: All subjects (n = 28) received 40 mg oral single-dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. RESULTS: Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax ) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration-time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24-h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0-4-h, 4-8-h and 0-24-h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. CONCLUSIONS: Sacubitril/valsartan reduced plasma Cmax and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (~2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentration-time curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat ~2.1-fold.

Effect of Sacubitril/Valsartan on Exercise-Induced Lipid Metabolism in Patients With Obesity and Hypertension.

Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3-2H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864.

The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study.

AIMS: Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated. Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan (LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV remodelling have not been investigated. METHODS AND RESULTS: This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to compare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCor® XCEL device at each time point. A total of 114 patients were included, with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (-6.36 vs. -2.32 g/m2; P = 0.039) and from baseline to 52 weeks (-6.83 vs. -3.55 g/m2; P = 0.029). These differences remained significant after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP (P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010). CONCLUSION: Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability.

Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
.

OBJECTIVES: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. METHODS: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. RESULTS: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. CONCLUSIONS: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
.

Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (~2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentration-time curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat ~2.1-fold.

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. METHODS: In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. RESULTS: Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and maximum plasma concentration (C max) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. CONCLUSION: The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

Assessment of Drug-Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects.

BACKGROUND AND OBJECTIVE: LCZ696 (sacubitril/valsartan), a novel angiotensin receptor neprilysin inhibitor has been recently approved for the treatment of patients with heart failure (HF) and reduced ejection fraction. As several HF patients are likely to use statins as co-medications, the potential for a pharmacokinetic drug-drug interaction between atorvastatin and LCZ696 was evaluated. METHODS: This was an open-label, three-period, single-sequence study in 28 healthy Chinese male subjects wherein LCZ696 200 mg was administered twice daily for 5 days in period 1. Following a washout period, atorvastatin 80 mg was administered once daily for 4 days (period 2) and subsequently co-administered with LCZ696 200 mg for 5 days (period 3). Serial plasma samples were collected to determine pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan) and atorvastatin and its metabolites. RESULTS: Atorvastatin co-administration had no effect on the pharmacokinetics of LBQ657, while the AUCτ,ss and C max,ss of sacubitril increased by 30 and 19 %, respectively, and the corresponding values for valsartan decreased by 19 and 9 %, respectively. Co-administration with LCZ696 increased C max,ss of atorvastatin, o-hydroxyatorvastatin, and p-hydroxyatorvastatin by 74, 68, and 108 %, respectively, and the AUCτ,ss of corresponding analytes increased by 34, 22, and 26 %, respectively. CONCLUSIONS: While atorvastatin had no significant impact on the pharmacokinetics of LCZ696 analytes upon co-administration, the C max of atorvastatin and its metabolites increased twofold, with a marginal increase in AUC (<1.3-fold). Multiple-dose administration of LCZ696 200 mg twice daily and atorvastatin 80 mg once daily either alone or in combination was generally safe and well tolerated in healthy subjects.

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVES: LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. METHODS: This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). RESULTS: Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. CONCLUSION: Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

Effects of Sacubitril/Valsartan (LCZ696) on Natriuresis, Diuresis, Blood Pressures, and NT-proBNP in Salt-Sensitive Hypertension.

Salt-sensitive hypertension (SSH) is characterized by impaired sodium excretion and subnormal vasodilatory response to salt loading. Sacubitril/valsartan (LCZ696) was hypothesized to increase natriuresis and diuresis and result in superior blood pressure control compared with valsartan in Asian patients with SSH. In this randomized, double-blind, crossover study, 72 patients with SSH received sacubitril/valsartan 400 mg and valsartan 320 mg once daily for 4 weeks each. SSH was diagnosed if the mean arterial pressure increased by ≥10% when patients switched from low (50 mmol/d) to high (320 mmol/d) sodium diet. The primary outcome was cumulative 6- and 24-hour sodium excretion after first dose administration. Compared with valsartan, sacubitril/valsartan was associated with a significant increase in natriuresis (adjusted treatment difference: 24.5 mmol/6 hours, 50.3 mmol/24 hours, both P<0.001) and diuresis (adjusted treatment difference: 291.2 mL/6 hours, P<0.001; 356.4 mL/24 hours, P=0.002) on day 1, but not on day 28, and greater reductions in office and ambulatory blood pressure on day 28. Despite morning dosing of both drugs, ambulatory blood pressure reductions were more pronounced at nighttime than at daytime or the 24-hour average. Compared with valsartan, sacubitril/valsartan significantly reduced N-terminal pro B-type natriuretic peptide levels on day 28 (adjusted treatment difference: -20%; P=0.001). Sacubitril/valsartan and valsartan were safe and well tolerated with no significant changes in body weight or serum sodium and potassium levels with either treatments. In conclusion, sacubitril/valsartan compared with valsartan was associated with short-term increases in natriuresis and diuresis, superior office and ambulatory blood pressure control, and significantly reduced N-terminal pro B-type natriuretic peptide levels in Asian patients with SSH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01681576.

Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects
.

OBJECTIVE: Sacubitril/valsartan (LCZ696) provides a novel therapeutic approach of neurohormonal modulation in heart failure via simultaneous inhibition of neprilysin and blockade of the angiotensin II type-1 receptor. This study was conducted to evaluate the effect of food on the oral bioavailability of LCZ696 analytes. MATERIALS AND METHODS: This was an open-label, randomized, 3-period crossover study in healthy subjects. Eligible subjects (N = 36) were randomized to 6 treatment sequences, each comprising 3 treatment periods during which subjects received a single oral dose of 400 mg LCZ696 under fasting condition and following a low- and high-fat meal. RESULTS: Following administration of LCZ696 after low- and high-fat meals, the mean Cmax of sacubitril and sacubitrilat (the active neprilysin inhibitor) decreased by 42 - 54% and 19 - 28%, respectively, while the tmax values increased. However, systemic exposure (AUCinf and AUClast) of sacubitril was slightly decreased (by 16% with low-fat meal) and that of sacubitrilat was unchanged in the presence of food. For valsartan, the Cmax decreased by ~ 40% when LCZ696 was administered after low- and high-fat meals. The systemic exposure of valsartan decreased by ~ 33% with a low-fat meal; however, it was unchanged with a high-fat meal. LCZ696 was generally safe and well tolerated in healthy subjects when administered under fasting or fed condition. CONCLUSION: Overall, administration of LCZ696 with meals decreased the rate and extent of absorption of sacubitril with little impact on the systemic exposure to sacubitrilat, its active metabolite. The systemic exposure to valsartan was decreased in the presence of food.
.

C-type natriuretic peptide and natriuretic peptide receptor B signalling inhibits cardiac sympathetic neurotransmission and autonomic function.

AIMS: B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPR-A) receptor signalling inhibits cardiac sympathetic neurotransmission, although C-type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesized that CNP acts similarly to BNP, and that transgenic rats (TGRs) with neuron-specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive. METHODS AND RESULTS: Mean arterial pressure and heart rate (HR) were significantly (P < 0.05) elevated in freely moving TGRs (n = 9) compared with Sprague Dawley (SD) controls (n = 10). TGR had impaired left ventricular systolic function and spectral analysis of HR variability suggested a shift towards sympathoexcitation. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase in stellate ganglia neurons. In SD rats, CNP (250 nM, n = 8) significantly reduced the tachycardia during right stellate ganglion stimulation (1-7 Hz) in vitro whereas the response to bath-applied norepinephrine (NE, 1 µM, n = 6) remained intact. CNP (250 nM, n = 8) significantly reduced the release of 3H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250 nM, n = 6). The neuronal Ca2+ current (n = 6) and intracellular Ca2+ transient (n = 9, using fura-2AM) were also reduced by CNP in isolated stellate neurons. Treatment of the TGR (n = 9) with the sympatholytic clonidine (125 µg/kg per day) significantly reduced mean arterial pressure and HR to levels observed in the SD (n = 9). CONCLUSION: C-type natriuretic peptide reduces cardiac sympathetic neurotransmission via a reduction in neuronal calcium signalling and NE release through the NPR-B receptor. Situations impairing CNP-NPR-B signalling lead to hypertension, tachycardia, and impaired left ventricular systolic function secondary to sympatho-excitation.

Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor.

PURPOSE: LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor, is indicated for chronic heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for HF. Following oral administration, LCZ696 provides systemic exposure to valsartan and sacubitril (a prodrug), and its metabolite sacubitrilat (the active neprilysin inhibitor, formerly named as LBQ657), which is eliminated primarily via renal route. Since renal dysfunction is a common comorbidity in patients with HF, two open-label studies assessing the effect of mild, moderate, and severe renal impairment were conducted. METHODS: Patients with mild (N = 8; creatinine clearance [CrCl] 50 to ≤80 mL/min), moderate (N = 8; CrCl 30 to <50 mL/min), and severe (N = 6; CrCl <30 mL/min) renal impairment and matching healthy subjects (CrCl >80 mL/min) for each severity group were enrolled to assess the pharmacokinetics of LCZ696 analytes following administration of LCZ696 400 mg once daily (QD) on days 1 and 5. RESULTS: The steady-state Cmax and AUC0-24h of sacubitril and valsartan were unchanged in patients with renal impairment compared with healthy subjects. However, the steady-state Cmax of sacubitrilat was increased by ∼60 % in patients irrespective of degree of renal impairment; half-life increased from 12 h (in healthy subjects) to 21.1, 23.7, and 38.5 h, respectively; and AUC0-24h was increased 2.10-, 2.24-, and 2.70-fold, respectively, in patients with mild, moderate, and severe renal impairment. CONCLUSION: Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan exposure. LCZ696 was generally well tolerated in patients with renal impairment.

Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 µg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.