Bruce C Trapnell, Brenna C Carey, Brian R Robinson
{"title":"健康人吸入莫格莫辛的药代动力学和药效学。","authors":"Bruce C Trapnell, Brenna C Carey, Brian R Robinson","doi":"10.1136/bmjresp-2024-002832","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Inhaled molgramostim, a form of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF), is a promising investigational pharmacotherapy for autoimmune pulmonary alveolar proteinosis (aPAP); however, its pharmacology in healthy subjects has not been reported.</p><p><strong>Methods: </strong>This randomised, double-blind, placebo-controlled, single-centre, phase 1 clinical trial assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy adults in single ascending dose (SAD) and multiple ascending dose (MAD) studies: one 150, 300 or 600 µg administration or six consecutive daily 300 or 600 µg administrations with evaluations over 28 or 34 days, respectively. The primary endpoint was safety, which was evaluated based on the number and severity of treatment-emergent AEs following single and multiple inhaled doses of molgramostim.</p><p><strong>Results: </strong>42 subjects were enrolled including 18 in the SAD study and 24 in the MAD study; all completed the study. Inhaled molgramostim in healthy people was well tolerated and no dose-limiting safety concerns or anti-drug antibody formation were observed in either study. GM-CSF was measurable in serum 30 min after administration of inhaled molgramostim, peaked at 2 hours for all three doses and had an elimination half-life of 1.7±0.0 to 5.9±0.9 hours in the SAD and MAD studies. Systemic GM-CSF exposure was non-linear in both the SAD and MAD studies. Inhaled molgramostim caused a rapid increase in white blood cells (WBC) counts and leucocyte subsets that normalised by 8 hours (SAD) or 15-21 days (MAD). Fractional exhaled nitric oxide remained within the normal range at all doses but was numerically, but not significantly, increased at the 600 μg dose.</p><p><strong>Conclusions: </strong>In healthy people, inhaled molgramostim was well-tolerated and resulted in systemic exposure at picogram levels, which had the expected PD effects on blood leucocyte levels that mostly remained within normal ranges.</p><p><strong>Trial registration number: </strong>NCT02468908; EudraCT No. 2013-001687-32.</p>","PeriodicalId":9048,"journal":{"name":"BMJ Open Respiratory Research","volume":"12 1","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458661/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy people.\",\"authors\":\"Bruce C Trapnell, Brenna C Carey, Brian R Robinson\",\"doi\":\"10.1136/bmjresp-2024-002832\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Inhaled molgramostim, a form of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF), is a promising investigational pharmacotherapy for autoimmune pulmonary alveolar proteinosis (aPAP); however, its pharmacology in healthy subjects has not been reported.</p><p><strong>Methods: </strong>This randomised, double-blind, placebo-controlled, single-centre, phase 1 clinical trial assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy adults in single ascending dose (SAD) and multiple ascending dose (MAD) studies: one 150, 300 or 600 µg administration or six consecutive daily 300 or 600 µg administrations with evaluations over 28 or 34 days, respectively. The primary endpoint was safety, which was evaluated based on the number and severity of treatment-emergent AEs following single and multiple inhaled doses of molgramostim.</p><p><strong>Results: </strong>42 subjects were enrolled including 18 in the SAD study and 24 in the MAD study; all completed the study. Inhaled molgramostim in healthy people was well tolerated and no dose-limiting safety concerns or anti-drug antibody formation were observed in either study. GM-CSF was measurable in serum 30 min after administration of inhaled molgramostim, peaked at 2 hours for all three doses and had an elimination half-life of 1.7±0.0 to 5.9±0.9 hours in the SAD and MAD studies. Systemic GM-CSF exposure was non-linear in both the SAD and MAD studies. Inhaled molgramostim caused a rapid increase in white blood cells (WBC) counts and leucocyte subsets that normalised by 8 hours (SAD) or 15-21 days (MAD). Fractional exhaled nitric oxide remained within the normal range at all doses but was numerically, but not significantly, increased at the 600 μg dose.</p><p><strong>Conclusions: </strong>In healthy people, inhaled molgramostim was well-tolerated and resulted in systemic exposure at picogram levels, which had the expected PD effects on blood leucocyte levels that mostly remained within normal ranges.</p><p><strong>Trial registration number: </strong>NCT02468908; EudraCT No. 2013-001687-32.</p>\",\"PeriodicalId\":9048,\"journal\":{\"name\":\"BMJ Open Respiratory Research\",\"volume\":\"12 1\",\"pages\":\"\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458661/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"BMJ Open Respiratory Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/bmjresp-2024-002832\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"BMJ Open Respiratory Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/bmjresp-2024-002832","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
Pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy people.
Background: Inhaled molgramostim, a form of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF), is a promising investigational pharmacotherapy for autoimmune pulmonary alveolar proteinosis (aPAP); however, its pharmacology in healthy subjects has not been reported.
Methods: This randomised, double-blind, placebo-controlled, single-centre, phase 1 clinical trial assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy adults in single ascending dose (SAD) and multiple ascending dose (MAD) studies: one 150, 300 or 600 µg administration or six consecutive daily 300 or 600 µg administrations with evaluations over 28 or 34 days, respectively. The primary endpoint was safety, which was evaluated based on the number and severity of treatment-emergent AEs following single and multiple inhaled doses of molgramostim.
Results: 42 subjects were enrolled including 18 in the SAD study and 24 in the MAD study; all completed the study. Inhaled molgramostim in healthy people was well tolerated and no dose-limiting safety concerns or anti-drug antibody formation were observed in either study. GM-CSF was measurable in serum 30 min after administration of inhaled molgramostim, peaked at 2 hours for all three doses and had an elimination half-life of 1.7±0.0 to 5.9±0.9 hours in the SAD and MAD studies. Systemic GM-CSF exposure was non-linear in both the SAD and MAD studies. Inhaled molgramostim caused a rapid increase in white blood cells (WBC) counts and leucocyte subsets that normalised by 8 hours (SAD) or 15-21 days (MAD). Fractional exhaled nitric oxide remained within the normal range at all doses but was numerically, but not significantly, increased at the 600 μg dose.
Conclusions: In healthy people, inhaled molgramostim was well-tolerated and resulted in systemic exposure at picogram levels, which had the expected PD effects on blood leucocyte levels that mostly remained within normal ranges.
期刊介绍：
BMJ Open Respiratory Research is a peer-reviewed, open access journal publishing respiratory and critical care medicine. It is the sister journal to Thorax and co-owned by the British Thoracic Society and BMJ. The journal focuses on robustness of methodology and scientific rigour with less emphasis on novelty or perceived impact. BMJ Open Respiratory Research operates a rapid review process, with continuous publication online, ensuring timely, up-to-date research is available worldwide. The journal publishes review articles and all research study types: Basic science including laboratory based experiments and animal models, Pilot studies or proof of concept, Observational studies, Study protocols, Registries, Clinical trials from phase I to multicentre randomised clinical trials, Systematic reviews and meta-analyses.
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