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Bioavailability Section

Effect of food on the oral bioavailability of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects 

Surya Ayalasomayajula, Thomas Langenickel, Priya Chandra, Edward Wolfson, Diego Albrecht, Wei Zhou, Parasar Pal, Iris Rajman, Gangadhar Sunkara

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Volume 54 p. 1012 - 1018

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 12/2016 (1012-1018)

Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects

Surya Ayalasomayajula¹, Thomas Langenickel², Priya Chandra¹, Edward Wolfson³, Diego Albrecht², Wei Zhou¹, Parasar Pal⁴, Iris Rajman², Gangadhar Sunkara¹ 

¹Novartis Institutes for BioMedical Research, East Hanover, NJ, USA,  ²Novartis Institutes for BioMedical Research, Basel, Switzerland,  ³Novartis Institutes for BioMedical Research, Cambridge, MA, USA, and ⁴Biostatistical Sciences, Novartis Healthcare Pvt. Ltd., Hyderabad, India
Objective: Sacubitril/valsartan (LCZ696) provides a novel therapeutic approach of neurohormonal modulation in heart failure via simultaneous inhibition of neprilysin and blockade of the angiotensin II type-1 receptor. This study was conducted to evaluate the effect of food on the oral bioavailability of LCZ696 analytes. Materials and methods: This was an open-label, randomized, 3-period crossover study in healthy subjects. Eligible subjects (N = 36) were randomized to 6 treatment sequences, each comprising 3 treatment periods during which subjects received a single oral dose of 400 mg LCZ696 under fasting condition and following a low- and high-fat meal. Results: Following administration of LCZ696 after low- and high-fat meals, the mean C_max of sacubitril and sacubitrilat (the active neprilysin inhibitor) decreased by 42 – 54% and 19 – 28%, respectively, while the t_max values increased. However, systemic exposure (AUC_inf and AUC_last) of sacubitril was slightly decreased (by 16% with low-fat meal) and that of sacubitrilat was unchanged in the presence of food. For valsartan, the C_max decreased by ~ 40% when LCZ696 was administered after low- and high-fat meals. The systemic exposure of valsartan decreased by ~ 33% with a low-fat meal; however, it was unchanged with a high-fat meal. LCZ696 was generally safe and well tolerated in healthy subjects when administered under fasting or fed condition. Conclusion: Overall, administration of LCZ696 with meals decreased the rate and extent of absorption of sacubitril with little impact on the systemic exposure to sacubitrilat, its active metabolite. The systemic exposure to valsartan was decreased in the presence of food. Correspondence to:
Surya Ayalasomayajula, MS, PhD 
Novartis Institutes for Biomedical Research
East Hanover, NJ, USA 
Email: surya.ayalasomayajula@ novartis.com

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