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Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects

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Abstract

Background and Objective

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects.

Methods

In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study.

Results

Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration (AUC0–last), and maximum plasma concentration (C max) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects.

Conclusion

The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

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Acknowledgments

Medical writing and editorial assistance was provided by Syed Abdul Haseeb (Novartis Healthcare Pvt. Ltd. Hyderabad, India). All the authors had full access to the study data, reviewed and critically revised the manuscript for content and approved the final version of the manuscript for submission.

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Author notes

  1. Wei Pan

    Present address: Shanghai Roche Pharmaceuticals Ltd., Shanghai, China

Authors and Affiliations

  1. Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Shanghai, China

    Yi Han, Wei Pan & Fan Yang

  2. Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, NJ, USA

    Surya Ayalasomayajula & Gangadhar Sunkara

  3. Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yaozong Yuan

  4. Translational Medicine, Clinical Pharmacology and Profiling, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland

    Thomas Langenickel & Markus Hinder

  5. Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India

    Sampath Kalluri & Parasar Pal

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  1. Yi Han
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Corresponding author

Correspondence to Surya Ayalasomayajula.

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Funding

This study was supported by Novartis Pharma AG, Basel, Switzerland.

Conflict of interest

YY declare that he has no conflict of interest pertaining to the current work. All the remaining authors were employees of Novartis Pharmaceutical Corporation at the time of the study conduct and may own company stocks.

Ethical approval

The study was conducted according to the ethical principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Independent Ethics Committee of Shanghai Ruijin Hospital. Written informed consent was obtained from all the subjects before performing any assessment.

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Han, Y., Ayalasomayajula, S., Pan, W. et al. Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects. Eur J Drug Metab Pharmacokinet 42, 109–116 (2017). https://doi.org/10.1007/s13318-016-0328-3

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