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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

Original Research

Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment 

Kenneth M. Kulmatycki, Thomas Langenickel, Wai Hong Ng, Parasar Pal, Wei Zhou, Tsu-Han Lin, Iris Rajman, Priyamvada Chandra, and Gangadhar Sunkara

Price
42.00 $

Price

42.00 $

Add to Cart ###ENGLISH_ABSTRACT_LINK### ###FREE_ENGLISH_ARTICLE_DOWNLIAD_LINK###

Volume 55 (2017) p. 728 - 739

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 9/2017 (728-739)

Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment 

Kenneth M. Kulmatycki¹, Thomas Langenickel², Wai Hong Ng³, Parasar Pal⁴, Wei Zhou³, Tsu-Han Lin³, Iris Rajman², Priyamvada Chandra³, and Gangadhar Sunkara³

¹Novartis Institutes for Biomedical Research, Cambridge, MA, USA, ²Novartis Institutes for BioMedical Research, Basel, Switzerland,  ³Novartis Institutes for Biomedical Research, East Hanover, NJ, USA, and  ⁴Novartis Healthcare Pvt. Ltd., Hyderabad, Telangana, India
Objectives: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. Methods: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Results: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril C_max increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, C_max was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 – 109%, respectively. Conclusions: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups. Correspondence to:
Kenneth M. Kulmatycki, PhD 
Novartis Institutes for Biomedical Research
220 Massachusetts Avenue, 342E
Cambridge, MA 02139, USA 
Email: [email protected]

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