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Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects
TD‐0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD‐0714 in rats resulted in dose‐dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours co...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719375/ https://www.ncbi.nlm.nih.gov/pubmed/32506827 http://dx.doi.org/10.1111/cts.12831 |
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author | Kanodia, Jitendra Lo, Arthur Baldwin, R. Michael Colley, Ken Zhou, Kefei Bourdet, David L. |
author_facet | Kanodia, Jitendra Lo, Arthur Baldwin, R. Michael Colley, Ken Zhou, Kefei Bourdet, David L. |
author_sort | Kanodia, Jitendra |
collection | PubMed |
description | TD‐0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD‐0714 in rats resulted in dose‐dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double‐blind, placebo controlled, single ascending dose (50–600 mg TD‐0714) and multiple ascending dose (10–200 mg TD‐0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD‐0714 was generally well‐tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD‐0714 exhibited dose‐proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50–100%) on day 14 for the entire 24‐hour interval indicating that sustained cGMP elevations are achieved at steady‐state. Maximal steady‐state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD‐0714 PK‐PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD‐0714 PK and PD profiles support further clinical development of TD‐0714 and suggest the potential for once‐daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function. |
format | Online Article Text |
id | pubmed-7719375 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77193752020-12-11 Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects Kanodia, Jitendra Lo, Arthur Baldwin, R. Michael Colley, Ken Zhou, Kefei Bourdet, David L. Clin Transl Sci Research TD‐0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD‐0714 in rats resulted in dose‐dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double‐blind, placebo controlled, single ascending dose (50–600 mg TD‐0714) and multiple ascending dose (10–200 mg TD‐0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD‐0714 was generally well‐tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD‐0714 exhibited dose‐proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50–100%) on day 14 for the entire 24‐hour interval indicating that sustained cGMP elevations are achieved at steady‐state. Maximal steady‐state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD‐0714 PK‐PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD‐0714 PK and PD profiles support further clinical development of TD‐0714 and suggest the potential for once‐daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function. John Wiley and Sons Inc. 2020-08-18 2020-11 /pmc/articles/PMC7719375/ /pubmed/32506827 http://dx.doi.org/10.1111/cts.12831 Text en © 2020 Theravance Biopharma US, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Kanodia, Jitendra Lo, Arthur Baldwin, R. Michael Colley, Ken Zhou, Kefei Bourdet, David L. Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects |
title | Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects |
title_full | Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects |
title_fullStr | Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects |
title_full_unstemmed | Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects |
title_short | Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects |
title_sort | safety, pharmacokinetics, and pharmacodynamics of td‐0714, a novel potent neprilysin inhibitor in healthy adult and elderly subjects |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719375/ https://www.ncbi.nlm.nih.gov/pubmed/32506827 http://dx.doi.org/10.1111/cts.12831 |
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