Cargando…

Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants

Sphingosine‐1‐phosphate (S1P) binding to the S1P‐1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS‐986166, a prodrug of t...

Descripción completa

Detalles Bibliográficos
Autores principales: Bihorel, Sébastien, Singhal, Shalabh, Shevell, Diane, Sun, Huadong, Xie, Jenny, Basdeo, Shenita, Liu, Ang, Dutta, Santanu, Ludwig, Elizabeth, Huang, Hannah, Lin, Kuan‐ju, Fura, Aberra, Throup, John, Girgis, Ihab G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821288/
https://www.ncbi.nlm.nih.gov/pubmed/33090733
http://dx.doi.org/10.1002/cpdd.878
_version_ 1783639389995270144
author Bihorel, Sébastien
Singhal, Shalabh
Shevell, Diane
Sun, Huadong
Xie, Jenny
Basdeo, Shenita
Liu, Ang
Dutta, Santanu
Ludwig, Elizabeth
Huang, Hannah
Lin, Kuan‐ju
Fura, Aberra
Throup, John
Girgis, Ihab G.
author_facet Bihorel, Sébastien
Singhal, Shalabh
Shevell, Diane
Sun, Huadong
Xie, Jenny
Basdeo, Shenita
Liu, Ang
Dutta, Santanu
Ludwig, Elizabeth
Huang, Hannah
Lin, Kuan‐ju
Fura, Aberra
Throup, John
Girgis, Ihab G.
author_sort Bihorel, Sébastien
collection PubMed
description Sphingosine‐1‐phosphate (S1P) binding to the S1P‐1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS‐986166, a prodrug of the active phosphorylated metabolite BMS‐986166‐P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS‐986166 versus placebo after single (0.75–5.0 mg) and repeated (0.25–1.5 mg/day) oral administration were assessed in healthy participants after a 1‐day lead‐in placebo period. A population model was developed to jointly describe BMS‐986166 and BMS‐986166‐P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS‐986166‐P concentrations and nadir of time‐matched (day –1) placebo‐corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5‐mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2‐bpm decrease in nDDHR over placebo.
format Online
Article
Text
id pubmed-7821288
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-78212882021-01-29 Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants Bihorel, Sébastien Singhal, Shalabh Shevell, Diane Sun, Huadong Xie, Jenny Basdeo, Shenita Liu, Ang Dutta, Santanu Ludwig, Elizabeth Huang, Hannah Lin, Kuan‐ju Fura, Aberra Throup, John Girgis, Ihab G. Clin Pharmacol Drug Dev Articles Sphingosine‐1‐phosphate (S1P) binding to the S1P‐1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS‐986166, a prodrug of the active phosphorylated metabolite BMS‐986166‐P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS‐986166 versus placebo after single (0.75–5.0 mg) and repeated (0.25–1.5 mg/day) oral administration were assessed in healthy participants after a 1‐day lead‐in placebo period. A population model was developed to jointly describe BMS‐986166 and BMS‐986166‐P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS‐986166‐P concentrations and nadir of time‐matched (day –1) placebo‐corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5‐mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2‐bpm decrease in nDDHR over placebo. John Wiley and Sons Inc. 2020-10-08 2021-01 /pmc/articles/PMC7821288/ /pubmed/33090733 http://dx.doi.org/10.1002/cpdd.878 Text en © 2020 Bristol Myers Squibb. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Articles
Bihorel, Sébastien
Singhal, Shalabh
Shevell, Diane
Sun, Huadong
Xie, Jenny
Basdeo, Shenita
Liu, Ang
Dutta, Santanu
Ludwig, Elizabeth
Huang, Hannah
Lin, Kuan‐ju
Fura, Aberra
Throup, John
Girgis, Ihab G.
Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants
title Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants
title_full Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants
title_fullStr Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants
title_full_unstemmed Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants
title_short Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants
title_sort population pharmacokinetic analysis of bms‐986166, a novel selective sphingosine‐1‐phosphate‐1 receptor modulator, and exposure‐response assessment of lymphocyte counts and heart rate in healthy participants
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821288/
https://www.ncbi.nlm.nih.gov/pubmed/33090733
http://dx.doi.org/10.1002/cpdd.878
work_keys_str_mv AT bihorelsebastien populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT singhalshalabh populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT shevelldiane populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT sunhuadong populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT xiejenny populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT basdeoshenita populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT liuang populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT duttasantanu populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT ludwigelizabeth populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT huanghannah populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT linkuanju populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT furaaberra populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT throupjohn populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants
AT girgisihabg populationpharmacokineticanalysisofbms986166anovelselectivesphingosine1phosphate1receptormodulatorandexposureresponseassessmentoflymphocytecountsandheartrateinhealthyparticipants