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

Ayalasomayajula, Surya; Langenickel, Thomas; Jordaan, Pierre; Zhou, Wei; Chandra, Priyamvada; Albrecht, Diego; Pal, Parasar; Rajman, Iris; Sunkara, Gangadhar

doi:10.1007/s00228-016-2072-7

Cited by 31 publications

(26 citation statements)

References 14 publications

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“…This was evidenced by the negative correlation of sacubitril AUC and creatinine clearance [45] and is consistent with similar observation in patients with renal impairment [44]. In contrast, the increase in the AUC and C max of sacubitril is not considered to be clinically relevant because sacubitril is an inactive prodrug.…”

Section: Patients With Hepatic Impairmentsupporting

confidence: 88%

“…The CL/F of valsartan (5.4 vs. 3.3 L/h), sacubitril (54.8 vs. 37.1 L/h), and sacubitrilat (0.7 vs. 0.4 L/h) in patients with HFrEF was approximately two-times lower than that observed in subjects without HFrEF (pooled data from three clinical pharmacology studies) [44,45]. The estimated half-life in patients with HFrEF was comparable but slightly higher to that observed in subjects without HFrEF for valsartan …”

Section: Pharmacokinetics In Patients With Heart Failurementioning

confidence: 95%

“…Compared with healthy subjects, the AUC to sacubitrilat was not impacted by mild (60-89 mL/ min/1.73 m 2 ) renal impairment (characterized using the Modification of Diet in Renal Disease formula [98]), whereas it was 2.3-, 2.9-, and 3.3-fold higher in patients with moderate-(30-59 mL/min/1.73 m 2 ) and severe (15-29 mL/min/1.73 m 2 ) renal impairment, and end-stage renal disease (15 mL/min/1.73 m 2 ) without dialysis, respectively (Fig. 3) [44]. No studies have been performed in patients undergoing dialysis.…”

Section: Patients With Renal Impairmentmentioning

confidence: 95%

“…Additional information in patients with HFrEF is available from the PARADIGM-HF trial cohort where 311 patients underwent sparse pharmacokinetic sampling (data on file), the data of which were compared with the pooled data from subjects without HFrEF (n = 38) in three clinical pharmacology studies [44,45]. The CL/F of valsartan (5.4 vs. 3.3 L/h), sacubitril (54.8 vs. 37.1 L/h), and sacubitrilat (0.7 vs. 0.4 L/h) in patients with HFrEF was approximately two-times lower than that observed in subjects without HFrEF (pooled data from three clinical pharmacology studies) [44,45].…”

Section: Pharmacokinetics In Patients With Heart Failurementioning

confidence: 99%

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

et al. 2017

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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 concentrationtime 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.The in-text citations in the tables were misaligned with the references in the original article. The full article with all the corrections is republished here.The online version of the original article can be found under

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Section: Patients With Hepatic Impairmentsupporting

confidence: 88%

Section: Pharmacokinetics In Patients With Heart Failurementioning

confidence: 95%

Section: Patients With Renal Impairmentmentioning

confidence: 95%

Section: Pharmacokinetics In Patients With Heart Failurementioning

confidence: 99%

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

et al. 2017

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“…Sacubitril is almost completely metabolized into its active form LBQ657 (also known as sacubitrilat) via ester hydrolysis, rapidly after ingestion [19]. In humans, sacubitril has a half life of 1.4 h, LBQ657 has a half life of 11.5 h and valsartan has a half life of 9.9 h. LBQ657 is excreted through urine, and the exposure to LBQ657 increases with decreasing renal function [20]. A decrease in renal function does not affect the pharmacokinetics of valsartan, since it is primarily excreted via the biliary route [21].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

From ARB to ARNI in Cardiovascular Control

et al. 2016

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Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition (‘ARNI’) with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria were reduced particularly in diabetic patients. The exact underlying mechanism remains unknown, but may involve improved renal haemodynamics and reduced glomerulosclerosis, e.g. related to a rise in natriuretic peptide levels. However, the assays of these peptides are hampered by methodological artefacts. Moreover, since sacubitrilat is largely renally cleared, drug accumulation may occur in patients with impaired renal function and thus hypotension is a potential side effect in patients with chronic kidney disease. Further caution is warranted since neprilysin also degrades endothelin-1 and amyloid beta in animal models. Accumulation of the latter may increase the risk of Alzheimer’s disease.

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A validated RP‐HPLC method for the evaluation of the influence of grapefruit juice on liver S9 activation of sacubitril

Moussa

Hashem

Mahrouse

et al. 2019

Biomedical Chromatography

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Grapefruit juice inhibits esterase enzyme. Therefore, a possible interaction with ester prodrugs should be taken into consideration. In this study, the influence of grapefruit juice on sacubitril (SAC) rat liver S9 activation by esterase enzyme was evaluated. An RP-HPLC method was developed and validated for estimation of SAC in rat liver S9 fraction using a C 18 Cyano column as stationary phase and acetonitrile-sodium dihydrogen phosphate buffer (0.02 M, pH 4 adjusted by o-phosphoric acid, 40:60, v/v), as mobile phase at a flow rate of 1 mL/min and UV detection at 254 nm. The method was successfully applied to an in vitro study in which SAC was incubated with rat liver S9 fraction prepared from rats that had previously ingested grapefruit juice for a week. The calculated SAC concentration after incubation was compared with that of SAC incubated with rat liver S9 fraction from the rat control group. The statistical significance between the results of test and control incubation sets was assessed. In conclusion, the current study demonstrated that grapefruit juice decreased SAC hydrolysis, hence delaying its activation to sacubitrilat (active form) in gut lumen. Based on this food-drug interaction, it may be required that grapefruit juice should be consumed with caution in patients receiving SAC.

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

Abstract: Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan exposure. LCZ696 was generally well tolerated in patients with renal impairment.

Cited by 31 publications

References 14 publications

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

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

From ARB to ARNI in Cardiovascular Control

A validated RP‐HPLC method for the evaluation of the influence of grapefruit juice on liver S9 activation of sacubitril

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