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Assessment of Drug–Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects

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Abstract

Background and Objective

LCZ696 (sacubitril/valsartan), a novel angiotensin receptor neprilysin inhibitor has been recently approved for the treatment of patients with heart failure (HF) and reduced ejection fraction. As several HF patients are likely to use statins as co-medications, the potential for a pharmacokinetic drug–drug interaction between atorvastatin and LCZ696 was evaluated.

Methods

This was an open-label, three-period, single-sequence study in 28 healthy Chinese male subjects wherein LCZ696 200 mg was administered twice daily for 5 days in period 1. Following a washout period, atorvastatin 80 mg was administered once daily for 4 days (period 2) and subsequently co-administered with LCZ696 200 mg for 5 days (period 3). Serial plasma samples were collected to determine pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan) and atorvastatin and its metabolites.

Results

Atorvastatin co-administration had no effect on the pharmacokinetics of LBQ657, while the AUCτ,ss and C max,ss of sacubitril increased by 30 and 19 %, respectively, and the corresponding values for valsartan decreased by 19 and 9 %, respectively. Co-administration with LCZ696 increased C max,ss of atorvastatin, o-hydroxyatorvastatin, and p-hydroxyatorvastatin by 74, 68, and 108 %, respectively, and the AUCτ,ss of corresponding analytes increased by 34, 22, and 26 %, respectively.

Conclusions

While atorvastatin had no significant impact on the pharmacokinetics of LCZ696 analytes upon co-administration, the C max of atorvastatin and its metabolites increased twofold, with a marginal increase in AUC (<1.3-fold). Multiple-dose administration of LCZ696 200 mg twice daily and atorvastatin 80 mg once daily either alone or in combination was generally safe and well tolerated in healthy subjects.

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Acknowledgments

The authors acknowledge Roohi Chopra (Novartis Healthcare Pvt. Ltd., Hyderabad) for providing medical writing and editorial support.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

    Surya Ayalasomayajula, Wei Zhou & Gangadhar Sunkara

  2. Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Shanghai, China

    Wei Pan & Yi Han

  3. Clinical Sciences and Innovation, Novartis Institutes for Biomedical Research, Shanghai, China

    Fan Yang

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

    Thomas Langenickel & Iris Rajman

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

    Parasar Pal

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

    Yaozong Yuan

Authors
  1. Surya Ayalasomayajula
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  2. Wei Pan
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  3. Yi Han
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  4. Fan Yang
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  10. Gangadhar Sunkara
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Corresponding author

Correspondence to Surya Ayalasomayajula.

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Funding

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

Conflict of interest

YY declares 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, Rujin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Written informed consent was obtained from all the subjects before performing any assessment.

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Ayalasomayajula, S., Pan, W., Han, Y. et al. Assessment of Drug–Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects. Eur J Drug Metab Pharmacokinet 42, 309–318 (2017). https://doi.org/10.1007/s13318-016-0349-y

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