Abstract
Purpose
LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor, is indicated for chronic heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for HF. Following oral administration, LCZ696 provides systemic exposure to valsartan and sacubitril (a prodrug), and its metabolite sacubitrilat (the active neprilysin inhibitor, formerly named as LBQ657), which is eliminated primarily via renal route. Since renal dysfunction is a common comorbidity in patients with HF, two open-label studies assessing the effect of mild, moderate, and severe renal impairment were conducted.
Methods
Patients with mild (N = 8; creatinine clearance [CrCl] 50 to ≤80 mL/min), moderate (N = 8; CrCl 30 to <50 mL/min), and severe (N = 6; CrCl <30 mL/min) renal impairment and matching healthy subjects (CrCl >80 mL/min) for each severity group were enrolled to assess the pharmacokinetics of LCZ696 analytes following administration of LCZ696 400 mg once daily (QD) on days 1 and 5.
Results
The steady-state Cmax and AUC0–24h of sacubitril and valsartan were unchanged in patients with renal impairment compared with healthy subjects. However, the steady-state Cmax of sacubitrilat was increased by ∼60 % in patients irrespective of degree of renal impairment; half-life increased from 12 h (in healthy subjects) to 21.1, 23.7, and 38.5 h, respectively; and AUC0–24h was increased 2.10-, 2.24-, and 2.70-fold, respectively, in patients with mild, moderate, and severe renal impairment.
Conclusion
Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan exposure. LCZ696 was generally well tolerated in patients with renal impairment.
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Acknowledgments
The authors would like to thank Dr. Sreedevi Boggarapu (Novartis Healthcare Pvt Ltd, Hyderabad) for providing medical writing support and editorial assistance with this manuscript and for the collation and incorporation of comments from all the authors.
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Two studies (EudraCT numbers: 2007-005480-96 [study 1] and 2007-005482-36 [study 2]) were conducted in compliance to the ethical principles originated from the Declaration of Helsinki, as well as Good Clinical Practices and applicable local regulatory requirements. The study protocols were approved by the Institutional Review Boards or Independent Ethics Committees including Ärztekammer Nordrhein (Germany) and Ethics Committee of the Clinical Center of Serbia (Serbia) for both the studies, and Ethics Committee under Federal Service on surveillance in healthcare and social development (Russia) for study 2. All the subjects provided written informed consent before enrolment in the study.
Disclosures
SA, TL, JP, DA, PP, IR, and GS are full-time employees of Novartis and eligible to receive Novartis stocks. PC was an employee of Novartis at the time of conduct of this study.
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Ayalasomayajula, S.P., Langenickel, T.H., Jordaan, P. et al. Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor. Eur J Clin Pharmacol 72, 1065–1073 (2016). https://doi.org/10.1007/s00228-016-2072-7
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DOI: https://doi.org/10.1007/s00228-016-2072-7