Parasar Pal

The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects

Aims LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with reduced ejection fraction. Neprilysin is one of multiple enzymes degrading amyloid‐β (Aβ). Its inhibition may increase Aβ levels. The potential exists that treatment of LCZ696, through the inhibition of neprilysin by LBQ657 (an LCZ696 metabolite), may result in accumulation of Aβ. The aim of this study was to assess the blood–brain‐barrier penetration of LBQ657 and the potential effects of LCZ696 on cerebrospinal fluid (CSF) concentrations of Aβ isoforms in healthy human volunteers. Methods In a double‐blind, randomized, parallel group, placebo‐controlled study, healthy subjects received once daily LCZ696 (400 mg, n = 21) or placebo (n = 22) for 14 days. Results LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable Aβ species 1–42 or 1–40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P = 0.919] and 1.05 [95% CI 0.82, 1.34; P = 0.702], respectively). A 42% increase in CSF AUEC(0,36 h) of soluble Aβ 1–38 was observed (estimated treatment ratio 1.42 [95% CI 1.05, 1.91; P = 0.023]). CSF levels of LBQ657 and CSF Aβ 1–42, 1–40, and 1–38 concentrations were not related (r 2 values 0.022, 0.010, and 0.008, respectively). Conclusions LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1–42 and 1–40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin. The clinical relevance of the increase in soluble CSF Aβ 1–38 is currently unknown.

The effect of LCZ696 on amyloid‐β concentrations in cerebrospinal fluid in healthy subjects

Aims LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with reduced ejection fraction. Neprilysin is one of multiple enzymes degrading amyloid‐β (Aβ). Its inhibition may increase Aβ levels. The potential exists that treatment of LCZ696, through the inhibition of neprilysin by LBQ657 (an LCZ696 metabolite), may result in accumulation of Aβ. The aim of this study was to assess the blood–brain‐barrier penetration of LBQ657 and the potential effects of LCZ696 on cerebrospinal fluid (CSF) concentrations of Aβ isoforms in healthy human volunteers. Methods In a double‐blind, randomized, parallel group, placebo‐controlled study, healthy subjects received once daily LCZ696 (400 mg, n = 21) or placebo (n = 22) for 14 days. Results LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable Aβ species 1–42 or 1–40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P = 0.919] and 1.05 [95% CI 0.82, 1.34; P = 0.702], respectively). A 42% increase in CSF AUEC(0,36 h) of soluble Aβ 1–38 was observed (estimated treatment ratio 1.42 [95% CI 1.05, 1.91; P = 0.023]). CSF levels of LBQ657 and CSF Aβ 1–42, 1–40, and 1–38 concentrations were not related (r 2 values 0.022, 0.010, and 0.008, respectively). Conclusions LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1–42 and 1–40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin. The clinical relevance of the increase in soluble CSF Aβ 1–38 is currently unknown.

Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction

Summary Aims Concomitant renin–angiotensin–aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF. Methods This was an open‐label, noncontrolled single‐sequence study. After a 24‐h run‐in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II–IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin‐converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]). Results On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio‐to‐baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P < 0.05). Plasma NT‐proBNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin‐1 levels significantly decreased on Day 21 (all, P < 0.05). Following administration of LCZ696, the Cmax of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100‐ and 200‐mg doses, the Cmax and AUC 0–12 h for sacubitril and LBQ657 were approximately dose‐proportional while that of valsartan was less than dose‐proportional. Conclusions Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.

Improved Insulin Sensitivity With Angiotensin Receptor Neprilysin Inhibition in Individuals With Obesity and Hypertension.

Natriuretic peptide (NP) deficiency and sustained renin‐angiotensin system activation are associated with impaired oxidative metabolism and predispose to type‐2 diabetes. We hypothesized that sacubitril/valsartan (LCZ696), which augments NP through neprilysin inhibition while blocking angiotensin II type‐1 (AT1)‐receptors, improves insulin sensitivity, lipid mobilization, and oxidation. After 8 weeks of treatment of obese patients with hypertension, sacubitril/valsartan 400 mg q.d., but not amlodipine 10 mg q.d., was associated with a significant increase from baseline in the insulin sensitivity index (hyperinsulinemic‐euglycemic clamp), and tended to be higher in patients treated with sacubitril/valsartan compared to amlodipine. Abdominal adipose tissue interstitial glycerol concentrations increased with sacubitril/valsartan, but decreased with amlodipine. Whole‐body lipolysis and substrate oxidation did not change with either treatment. Results confirm that sacubitril/valsartan treatment leads to a metabolic benefit in the study population and supports the relevance of neprilysin inhibition along with AT1‐receptor blockade in the regulation of human glucose and lipid metabolism.

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.

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.

Pharmacokinetic drug–drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol

LCZ696 is a first‐in‐class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug–drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open‐label, single‐sequence, 3‐period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]‐ and S[−]‐carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80–1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)‐ and S(−)‐carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug–drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Assessment of Drug Interaction Potential between LCZ696, an Angiotensin Receptor Neprilysin Inhibitor, and Digoxin or Warfa rin

LCZ696 (sacubitril/valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that simultaneously inhibits neprilysin and blocks the angiotensin II receptor. LCZ696 has been recently approved for treatment of HF and likely be co-administered with digoxin or warfarin. The drug interaction potential between LCZ696 and digoxin or warfarin was evaluated because of their potentially shared metabolic/elimination pathways. Two separate drug-drug interaction studies were conducted in healthy subjects: LCZ696 200 mg twice daily was co-administered with digoxin 0.25 mg once daily (n=24) and warfarin 25 mg single dose (n=26), respectively. The pharmacokinetic profiles of the LCZ696 analytes (sacubitril, LBQ657 and valsartan), digoxin and R- and S-warfarin, the pharmacodynamic effects of warfarin and the safety and tolerability of the investigational drugs were assessed. The geometric mean ratio (GMR) and 90%confidence interval (90% CI) for Cmax and AUCs of R- and S-warfarin, digoxin, and pharmacologically active LCZ696 analytes were within the bioequivalence range of 0.8-1.25 when co-administered. The GMR and 90% CI of warfarin pharmacodynamics effects were also within 0.8-1.25 range when co-administered with LCZ696. LCZ696 was generally safe and welltolerated when administered alone or in combination with digoxin/warfarin. No drug-drug interaction was observed upon co-administration of LCZ696 with digoxin/warfarin in healthy subjects.

Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium.

OBJECTIVE Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor. METHODS In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 μg glycopyrronium was inhaled alone and on Day 4 of a 6-day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout cimetidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrronium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast), and renal clearance (CLr) of glycopyrronium. RESULTS Cimetidine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyrronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12 - 1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70 - 0.85). Cmax was not affected. Both treatments were safe and well tolerated without any deaths or severe adverse events. CONCLUSION Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.

Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study.

OBJECTIVE Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects. METHODS This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 µg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability. RESULTS A total of 73 healthy male (n = 35) and female (n = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 minutes, with the upper limit of the two-sided 90% confidence interval (CI) being 4.80 ms, excluding a relevant QT effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of -2.88 (90% CI: -3.78, -1.99) beats per minutes (bpm) and a maximum of -5.87 (90% CI: -7.82, -3.92) bpm at 5 hours post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median tmax = 7 minutes). All the treatments were well tolerated with no serious adverse events. CONCLUSION A supra-therapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval.