The Experts below are selected from a list of 20904 Experts worldwide ranked by ideXlab platform
Gangadhar Sunkara - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacodynamic interaction between intravenous nitroglycerin and oral sacubitril/Valsartan (LCZ696) in healthy subjects.
European Journal of Clinical Pharmacology, 2018Co-Authors: Uwe Schuehly, Surya Ayalasomayajula, Georg Golor, Margaret F. Prescott, Markus Hinder, Gangadhar Sunkara, Jeppe Buchbjerg, Thomas LangenickelAbstract: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. 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. 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. 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.
-
Pharmacokinetics and safety of sacubitril/Valsartan (LCZ696) in patients with mild and moderate hepatic impairment .
International journal of clinical pharmacology and therapeutics, 2017Co-Authors: Kenneth Kulmatycki, Thomas Langenickel, Wai Hong Ng, Iris Rajman, Priyamvada Chandra, Wei Zhou, Gangadhar SunkaraAbstract: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. .
-
Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical pharmacokinetics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract: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.
-
Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical Pharmacokinectics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract: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.
-
Effect of food on the oral bioavailability of amlodipine/Valsartan and amlodipine/Valsartan/hydrochlorothiazide fixed dose combination tablets in healthy subjects.
Clinical pharmacology in drug development, 2014Co-Authors: Gangadhar Sunkara, Surya Ayalasomayajula, Xuemin Jiang, Christine Reynolds, Denise Serra, Yiming Zhang, Monica Ligueros-saylan, Serge Winter, Venkateswar JarugulaAbstract:A double fixed dose combination of amlodipine/Valsartan and triple fixed dose combination of amlodipine/Valsartan/HCTZ tablets have been developed to treat patients with moderate-to-severe hypertension. Here, we present the effect of food on the oral bioavailability of these two fixed dose combination tablets from two separate clinical studies in healthy subjects. Single oral doses of amlodipine/Valsartan (10/160 mg) and amlodipine/Valsartan/HCTZ (10/320/25 mg were administered under fasted or fed conditions. Blood samples were collected in both studies to determine the pharmacokinetic parameters of amlodipine, Valsartan, and/or HCTZ using non-compartmental analysis. Following amlodipine/Valsartan administration, the geometric mean ratios (GMRs, 90% CI) of AUC0-∞ and Cmax were 1.09 (1.05-1.13) and 1.03 (0.97-1.09) for amlodipine, and 0.94 (0.81-1.10) and 0.86 (0.73-1.02) for Valsartan, respectively. Following amlodipine/Valsartan/HCTZ administration, the GMRs (90%CI) of AUC0-∞ and Cmax were 1.09 (1.04-1.15) and 1.11 (1.05-1.08) for amlodipine, 1.14 (0.99-1.31) and 1.12 (0.98-1.29) for Valsartan, and 1.09 (1.02-1.16) and 0.86 (0.79-0.93) for HCTZ, respectively. Considering the sample size and pharmacokinetic variability associated with analytes, these study results indicate that food effect is minimal or none when fixed dose combination tablets are administered with food. In conclusion, both fixed dose combination tablets can be administered without regards to meals.
Thomas Langenickel - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacodynamic interaction between intravenous nitroglycerin and oral sacubitril/Valsartan (LCZ696) in healthy subjects.
European Journal of Clinical Pharmacology, 2018Co-Authors: Uwe Schuehly, Surya Ayalasomayajula, Georg Golor, Margaret F. Prescott, Markus Hinder, Gangadhar Sunkara, Jeppe Buchbjerg, Thomas LangenickelAbstract: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. 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. 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. 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.
-
Pharmacokinetics and safety of sacubitril/Valsartan (LCZ696) in patients with mild and moderate hepatic impairment .
International journal of clinical pharmacology and therapeutics, 2017Co-Authors: Kenneth Kulmatycki, Thomas Langenickel, Wai Hong Ng, Iris Rajman, Priyamvada Chandra, Wei Zhou, Gangadhar SunkaraAbstract: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. .
-
Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical pharmacokinetics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract: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.
-
Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical Pharmacokinectics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract: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.
-
effects of sacubitril Valsartan lcz696 on natriuresis diuresis blood pressures and nt probnp in salt sensitive hypertension
Hypertension, 2017Co-Authors: Tzungdau Wang, Margaret F. Prescott, Markus Hinder, Mooyong Rhee, Elizabeth Hirschhorn, Brian Tomlinson, Fan Yang, Thomas LangenickelAbstract: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: . Unique identifier: [NCT01681576][1]. # Novelty and Significance {#article-title-41} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01681576&atom=%2Fhypertensionaha%2F69%2F1%2F32.atom
Lourdes Vicent - One of the best experts on this subject based on the ideXlab platform.
-
Ventricular Arrhythmic Storm after Initiating Sacubitril/Valsartan.
The Cardiology, 2018Co-Authors: Lourdes Vicent, Miriam Juarez, Vanesa Bruna, Carolina Devesa, Hugo González-saldívar, Iago Sousa-casasnovas, Irene Martin, Jorge Garcia, Francisco Fernández-avilés, Manuel Martínez-sellésAbstract:Objectives: Sacubitril/Valsartan was approved recently for the treatment of patients with heart failure and reduced ejection fraction. We present 6 cases of ventricular arrhythmia, that occurred shortly after sacubitril/Valsartan initiation, that required drug withdrawal. Other potential triggering factors of electrical storm were ruled out and, from the arrhythmic perspective, all of the patients were stable in the previous year. Our aim is to describe the possible association of sacubitril/Valsartan with arrhythmic storm. Methods: This was an observational monocentric study performed in the first 7 months of sacubitril/Valsartan commercialization in Spain (October 2016). All patients were included in the SUMA (Sacubitril/Varsartan Usado Ambulatoriamente en Madrid [Sacubitril/Valsartan Used in Outpatients in Madrid]) registry. Patients were consecutively enrolled on the day they started the drug. Ventricular arrhythmic storm was defined as ≥2 episodes of sustained ventricular arrhythmia or defibrillator therapy application in 24 h. Results: From 108 patients who received the drug, 6 presented with ventricular arrhythmic storm (5.6%). Baseline characteristics were similar in the patients with and without ventricular arrhythmic storm. The total number of days that sacubitril/Valsartan was administered to each patient was 5, 6, 44 (8 since titration), 84, 93, and 136 (105 since titration), respectively. Conclusions: Our data are not enough to infer a cause-and-effect relationship. Further investigations regarding a potential proarrhythmic effect of sacubitril/Valsartan are probably needed.
-
ventricular arrhythmic storm after initiating sacubitril Valsartan
The Cardiology, 2018Co-Authors: Lourdes Vicent, Miriam Juarez, Hugo Gonzalezsaldivar, Vanesa Bruna, Carolina Devesa, Iago Sousacasasnovas, Francisco Fernandezaviles, Irene Martin, Jorge Garcia, Manuel MartinezsellesAbstract:Objectives: Sacubitril/Valsartan was approved recently for the treatment of patients with heart failure and reduced ejection fraction. We present 6 cases of ventricular arrhythmia, that occurred shortly after sacubitril/Valsartan initiation, that required drug withdrawal. Other potential triggering factors of electrical storm were ruled out and, from the arrhythmic perspective, all of the patients were stable in the previous year. Our aim is to describe the possible association of sacubitril/Valsartan with arrhythmic storm. Methods: This was an observational monocentric study performed in the first 7 months of sacubitril/Valsartan commercialization in Spain (October 2016). All patients were included in the SUMA (Sacubitril/Varsartan Usado Ambulatoriamente en Madrid [Sacubitril/Valsartan Used in Outpatients in Madrid]) registry. Patients were consecutively enrolled on the day they started the drug. Ventricular arrhythmic storm was defined as ≥2 episodes of sustained ventricular arrhythmia or defibrillator therapy application in 24 h. Results: From 108 patients who received the drug, 6 presented with ventricular arrhythmic storm (5.6%). Baseline characteristics were similar in the patients with and without ventricular arrhythmic storm. The total number of days that sacubitril/Valsartan was administered to each patient was 5, 6, 44 (8 since titration), 84, 93, and 136 (105 since titration), respectively. Conclusions: Our data are not enough to infer a cause-and-effect relationship. Further investigations regarding a potential proarrhythmic effect of sacubitril/Valsartan are probably needed.
Surya Ayalasomayajula - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacodynamic interaction between intravenous nitroglycerin and oral sacubitril/Valsartan (LCZ696) in healthy subjects.
European Journal of Clinical Pharmacology, 2018Co-Authors: Uwe Schuehly, Surya Ayalasomayajula, Georg Golor, Margaret F. Prescott, Markus Hinder, Gangadhar Sunkara, Jeppe Buchbjerg, Thomas LangenickelAbstract: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. 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. 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. 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.
-
Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical pharmacokinetics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract: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.
-
Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical Pharmacokinectics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract: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.
-
Effect of food on the oral bioavailability of amlodipine/Valsartan and amlodipine/Valsartan/hydrochlorothiazide fixed dose combination tablets in healthy subjects.
Clinical pharmacology in drug development, 2014Co-Authors: Gangadhar Sunkara, Surya Ayalasomayajula, Xuemin Jiang, Christine Reynolds, Denise Serra, Yiming Zhang, Monica Ligueros-saylan, Serge Winter, Venkateswar JarugulaAbstract:A double fixed dose combination of amlodipine/Valsartan and triple fixed dose combination of amlodipine/Valsartan/HCTZ tablets have been developed to treat patients with moderate-to-severe hypertension. Here, we present the effect of food on the oral bioavailability of these two fixed dose combination tablets from two separate clinical studies in healthy subjects. Single oral doses of amlodipine/Valsartan (10/160 mg) and amlodipine/Valsartan/HCTZ (10/320/25 mg were administered under fasted or fed conditions. Blood samples were collected in both studies to determine the pharmacokinetic parameters of amlodipine, Valsartan, and/or HCTZ using non-compartmental analysis. Following amlodipine/Valsartan administration, the geometric mean ratios (GMRs, 90% CI) of AUC0-∞ and Cmax were 1.09 (1.05-1.13) and 1.03 (0.97-1.09) for amlodipine, and 0.94 (0.81-1.10) and 0.86 (0.73-1.02) for Valsartan, respectively. Following amlodipine/Valsartan/HCTZ administration, the GMRs (90%CI) of AUC0-∞ and Cmax were 1.09 (1.04-1.15) and 1.11 (1.05-1.08) for amlodipine, 1.14 (0.99-1.31) and 1.12 (0.98-1.29) for Valsartan, and 1.09 (1.02-1.16) and 0.86 (0.79-0.93) for HCTZ, respectively. Considering the sample size and pharmacokinetic variability associated with analytes, these study results indicate that food effect is minimal or none when fixed dose combination tablets are administered with food. In conclusion, both fixed dose combination tablets can be administered without regards to meals.
Lars Kober - One of the best experts on this subject based on the ideXlab platform.
-
effects of sacubitril Valsartan on n terminal pro b type natriuretic peptide in heart failure with preserved ejection fraction
Jacc-Heart Failure, 2020Co-Authors: Jonathan W Cunningham, Pardeep S Jhund, Stefan Janssens, Brian Claggett, Milton Packer, Inder S Anand, Muthiah Vaduganathan, Michael R Zile, Faiez Zannad, Lars KoberAbstract:Abstract Objectives The authors sought to evaluate the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/Valsartan, and the treatment effect of sacubitril/Valsartan on NT-proBNP overall and in key subgroups. Background Sacubitril/Valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with Valsartan in patients with HF with preserved EF (HFpEF). Methods In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/Valsartan or Valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential Valsartan and sacubitril/Valsartan run-in periods, and 16 and 48 weeks post-randomization. Results Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. Conclusions Baseline NT-proBNP predicted HF events but did not modify the sacubitril/Valsartan treatment effect in patients with HFpEF. Sacubitril/Valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
-
Valsartan: the past, present and future.
Future cardiology, 2005Co-Authors: Lars Kober, Christian Torp-pedersenAbstract:Valsartan (Diovan®) is a widely use angiotensin receptor blocker that prevents angiotensin II from binding to the subtype 1 receptor. Stimulation of the subtype 1 receptor is believed to mediate many of the deleterious effects accompanied by increased angiotensin II levels. Valsartan is effective in the treatment of hypertension, alone and in combination with hydrochlorothiazide. Valsartan is similarly as effective as angiotensin-converting enzyme (ACE) blockers following myocardial infarction accompanied with left ventricular dysfunction, and/or heart failure. For the treatment of congestive heart failure with left ventricular dysfunction, Valsartan offers a reduction in mortality in patients not able to tolerate an ACE inhibitor and in combination with an ACE inhibitor, Valsartan reduces morbidity (hospitalization for heart failure).
-
Valsartan captopril or both in myocardial infarction complicated by heart failure left ventricular dysfunction or both
The New England Journal of Medicine, 2003Co-Authors: Marc A Pfeffer, John J V Mcmurray, Jean-lucien Rouleau, Karl Swedberg, Lars Kober, Eric J Velazquez, Aldo P Maggioni, Scott D Solomon, Frans Van De Werf, Harvey D WhiteAbstract:background Angiotensin-converting–enzyme (ACE) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. In a double-blind trial, we compared the effect of the angiotensin-receptor blocker Valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in this population of patients. methods Patients receiving conventional therapy were randomly assigned, 0.5 to 10 days after acute myocardial infarction, to additional therapy with Valsartan (4909 patients), Valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause. results During a median follow-up of 24.7 months, 979 patients in the Valsartan group died, as did 941 patients in the Valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the Valsartan group as compared with the captopril group, 1.00; 97.5 percent confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the Valsartanand-captopril group as compared with the captopril group, 0.98; 97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the Valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001). The Valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the Valsartan group, and cough, rash, and taste disturbance were more common in the captopril group. conclusions Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining Valsartan with captopril increased the rate of adverse events without improving survival.
