Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization

Purpose: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II–IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization. Method: This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett’s correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety. Results: Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups. Conclusion: Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines

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

Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure

The natriuretic peptide system exerts beneficial cardiorenal effects in chronic heart failure, whereas activation of the renin–angiotensin–aldosterone system exerts opposing and deleterious effects. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, targets both neurohormonal systems by inhibiting neprilysin, which prevents natriuretic peptide degradation, while concomitantly blocking the angiotensin (AT1) receptor. In clinical studies of patients with chronic heart failure with reduced and preserved left ventricular ejection fraction, LCZ696 has been shown to improve biomarkers of cardiorenal function. The effects of LCZ696 on cardiovascular outcomes and survival in patients with heart failure are currently being investigated

Pharmacokinetics after single ascending dose, food effect, and safety of sacubitril/valsartan (LCZ696), a novel angiotensin receptor and neprilysin inhibitor, in healthy Japanese subjects

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. 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, LBQ657 [sacubitrilat], and valsartan). 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%, 10%, and 40%, respectively, and Cmax by 72%, 27%, and 51% respectively. Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects

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, f$_{max}$, was extracted and expected limits for the general population were inferred. RESULTS In the healthy subject cohort, significantly different f$_{max}$ values were found across the different body locations, but they were nonsignificant across modalities. No significant correlation was found with heart rate. The measured f$_{max}$ 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)

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 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

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