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

Akahori, Mizuki; Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Sunkara, Gangadhar

doi:10.1007/s13318-016-0354-1

Cited by 13 publications

(14 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Valsartan is a strongly pH-dependent solubility drug, of which the absorption window is stomach and upper part of small intestine. Thus, absorption rate of valsartan could be decreased when it is taken with food in advance, as well as the exposure of valsartan is reduced 39 . For insights of effects to bioavailability of drugs by food, data sets for oral valsartan administered either fasted or fed were used for pharmacokinetic modeling.…”

Section: Discussionmentioning

confidence: 99%

Identification of beagle food taking patterns and protocol for food effects evaluation on bioavailability

Zhang

Wang

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Food is a known primary role to the exposure of the drugs orally administered. Since each animal may have unique food taking pattern and it is difficult to manipulate the food taking to animals, there lacks rationalized protocol for the food effects in pre-clinic study. The objective of this study was to identify the beagle food taking patterns and demonstrate their effects on bioavailability in valsartan. Herein, four types of food taking patterns of beagle were identified via inter-day and intra-day analysis, and named as Persisting, Pulsing, Postponing, Pushing (“4P Modes”), respectively, which were also validated by principal component analysis (PCA). Interestingly, food intake resulted in a reduced area under the concentration-time curve (AUC0–12h), maximum concentration (Cmax) and absorption rate, whilst the reduction varied in “4P Modes” of food taking. General considerations in the design of experiment for food effect to the bioavailability in beagles have been established as: to recognize the food taking patterns in each animal, to confirm the inter-day stability of the food taking behaviors, to trace the food taking patterns in parallel with plasma sampling. In conclusion, the right animals with proper food taking patterns should be assessed and selected for pre-clinic bioavailability evaluations.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of beagle food taking patterns and protocol for food effects evaluation on bioavailability

Zhang

Wang

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In one constituent study, the pharmacokinetics of Entresto following single ascending doses were only measured in healthy males (40 males enrolled). 61 In another constituent study, 29 males and 25 females were included, however sex-dependent analysis was conducted by pooling both young (18-45 years old) and elderly (≥65 years old) volunteers together, which could be confounded by menopause status (pre-, peri-& post-). 62 Sex-independent data within the same study demonstrated that Entresto clearance was significantly reduced with age.…”

Section: Sex Differences In Heart Failure Etiologiesmentioning

confidence: 99%

Exploring the Food and Drug Administration’s review and approval of Entresto (sacubitril/valsartan)

Eadie

Brunt

Herder

2021

Pharmacology Res & Perspec

View full text Add to dashboard Cite

The discussions, processes, and procedural decisions documented in regulatory decisions can offer unique insight into a pharmaceutical's strengths, weaknesses, or residual knowledge gaps; yet these resources are often overlooked. From a research perspective, the disclosure of regulatory agency reviews, procedures and evidence holds significant value as the information contained within such documents is often more extensive than what is reported in the primary medical literature or continuing medical education. [1][2][3][4][5] As a result,

show abstract

“…The effect of food on the pharmacokinetics of all the analytes (Table 3) was evaluated in healthy subjects following administrations of sacubitril/valsartan 400 mg with a low-fat meal (500-600 kcal) and a high-fat meal (800-1000 kcal) [24] and 200 mg of sacubitril/valsartan with a Japanese meal (*500 kcal, 14% fat) [30]. Administration of sacubitril/valsartan with food resulted in a decreased rate of absorption of sacubitril, as indicated by a delayed T max (by 1-2 h) and a decreased C max (by 48-72%).…”

Section: Effect Of Foodmentioning

confidence: 99%

“…Therefore, sacubitril/valsartan can be administered without regard to meals. Single-dose pharmacokinetics: data of sacubitril/valsartan 200 mg were pooled from five studies in healthy subjects [21,30,45,100; data on file for furosemide study (CLCZ696B2126) study]…”

Section: Effect Of Foodmentioning

confidence: 99%

“…and data of sacubitril/valsartan 400 mg data were pooled from seven studies [21,24,30,49,94,100,101]. Steady-state representative pharmacokinetics: data of sacubitril/valsartan 400 mg QD in healthy subjects was reported by Gan et al [49]; data of sacubitril/valsartan 200 mg in healthy subjects data were pooled from five studies [25,29] (data on file for two studies including DDI study with furosemide and nitroglycerine, EudraCT no.…”

Section: Effect Of Foodmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

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

show abstract

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

Abstract: Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

Cited by 13 publications

References 15 publications

Identification of beagle food taking patterns and protocol for food effects evaluation on bioavailability

Identification of beagle food taking patterns and protocol for food effects evaluation on bioavailability

Exploring the Food and Drug Administration’s review and approval of Entresto (sacubitril/valsartan)

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

Contact Info

Product

Resources

About