New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans
BMS-986120 is a novel first-in-class oral protease-activated receptor 4 (PAR4) antagonist exhibiting robust antithrombotic activity that has shown low bleeding risk in monkeys. We sought to assess pharmacokinetics, pharmacodynamics, and tolerability of BMS-986120 in healthy participants and platelet...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-10-01
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| Series: | Platelets |
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| Online Access: | http://dx.doi.org/10.1080/09537104.2022.2088719 |
| _version_ | 1797684126717837312 |
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| author | Samira Merali Zhaoqing Wang Charles Frost Mario Callejo Michael Hedrick Lester Hui Stephanie Meadows Shropshire Ke Xu Michel Bouvier Mary M. DeSouza Jing Yang |
| author_facet | Samira Merali Zhaoqing Wang Charles Frost Mario Callejo Michael Hedrick Lester Hui Stephanie Meadows Shropshire Ke Xu Michel Bouvier Mary M. DeSouza Jing Yang |
| author_sort | Samira Merali |
| collection | DOAJ |
| description | BMS-986120 is a novel first-in-class oral protease-activated receptor 4 (PAR4) antagonist exhibiting robust antithrombotic activity that has shown low bleeding risk in monkeys. We sought to assess pharmacokinetics, pharmacodynamics, and tolerability of BMS-986120 in healthy participants and platelet responses to BMS-986120 in participants carrying PAR4 A120T variants. Phase I, randomized, double-blind, placebo-controlled single-ascending-dose (SAD; N = 56) and multiple-ascending-dose (MAD; N = 32) studies were conducted. Exposure was approximately dose-proportional: maximum concentrations 27.3 and 1536 ng/mL, areas under the curve (AUC) to infinity of 164 and 15,603 h*ng/mL, and half-lives of 44.7 and 84.1 hours for 3.0 and 180 mg, respectively. The accumulation index suggested an ~2-fold AUC increase at steady state. Single doses of 75 and 180 mg BMS-986120 produced ≥80% inhibition of 12.5 μM PAR4 agonist peptide (AP)-induced platelet aggregation through at least 24 hours postdose, and doses ≥10 mg for ~7 days inhibited aggregation completely through 24 hours. No differences in PAR4-mediated platelet response were seen between AA120 versus TT120 PAR4 variants. In cells expressing A120 or T120 PAR4 proteins, no differences in half-maximal effective concentration in receptor activation by PAR4-AP were observed. BMS-986120 was well tolerated with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02208882. |
| first_indexed | 2024-03-12T00:25:00Z |
| format | Article |
| id | doaj.art-47ad41e68b7743679c9d02c11b017d54 |
| institution | Directory Open Access Journal |
| issn | 0953-7104 1369-1635 |
| language | English |
| last_indexed | 2024-03-12T00:25:00Z |
| publishDate | 2022-10-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Platelets |
| spelling | doaj.art-47ad41e68b7743679c9d02c11b017d542023-09-15T10:38:11ZengTaylor & Francis GroupPlatelets0953-71041369-16352022-10-0133796997810.1080/09537104.2022.20887192088719New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humansSamira Merali0Zhaoqing Wang1Charles Frost2Mario Callejo3Michael Hedrick4Lester Hui5Stephanie Meadows Shropshire6Ke Xu7Michel Bouvier8Mary M. DeSouza9Jing Yang10Bristol Myers SquibbBristol Myers SquibbBristol Myers SquibbUniversité de MontréalBristol Myers SquibbBristol Myers SquibbBristol Myers SquibbBristol Myers SquibbUniversité de MontréalBristol Myers SquibbBristol Myers SquibbBMS-986120 is a novel first-in-class oral protease-activated receptor 4 (PAR4) antagonist exhibiting robust antithrombotic activity that has shown low bleeding risk in monkeys. We sought to assess pharmacokinetics, pharmacodynamics, and tolerability of BMS-986120 in healthy participants and platelet responses to BMS-986120 in participants carrying PAR4 A120T variants. Phase I, randomized, double-blind, placebo-controlled single-ascending-dose (SAD; N = 56) and multiple-ascending-dose (MAD; N = 32) studies were conducted. Exposure was approximately dose-proportional: maximum concentrations 27.3 and 1536 ng/mL, areas under the curve (AUC) to infinity of 164 and 15,603 h*ng/mL, and half-lives of 44.7 and 84.1 hours for 3.0 and 180 mg, respectively. The accumulation index suggested an ~2-fold AUC increase at steady state. Single doses of 75 and 180 mg BMS-986120 produced ≥80% inhibition of 12.5 μM PAR4 agonist peptide (AP)-induced platelet aggregation through at least 24 hours postdose, and doses ≥10 mg for ~7 days inhibited aggregation completely through 24 hours. No differences in PAR4-mediated platelet response were seen between AA120 versus TT120 PAR4 variants. In cells expressing A120 or T120 PAR4 proteins, no differences in half-maximal effective concentration in receptor activation by PAR4-AP were observed. BMS-986120 was well tolerated with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02208882.http://dx.doi.org/10.1080/09537104.2022.2088719antiplateletpharmacokineticsclinical trialplatelet |
| spellingShingle | Samira Merali Zhaoqing Wang Charles Frost Mario Callejo Michael Hedrick Lester Hui Stephanie Meadows Shropshire Ke Xu Michel Bouvier Mary M. DeSouza Jing Yang New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans Platelets antiplatelet pharmacokinetics clinical trial platelet |
| title | New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans |
| title_full | New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans |
| title_fullStr | New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans |
| title_full_unstemmed | New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans |
| title_short | New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans |
| title_sort | new oral protease activated receptor 4 antagonist bms 986120 tolerability pharmacokinetics pharmacodynamics and gene variant effects in humans |
| topic | antiplatelet pharmacokinetics clinical trial platelet |
| url | http://dx.doi.org/10.1080/09537104.2022.2088719 |
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