Lisbet Westergaard, Lene Alifrangis, Stephen T Buckley, Hans Veit Coester, Thomas Klitgaard, Niels R Kristensen, Erica Nishimura, Lea Nørgreen, Thaís M P Rocha, Dorte B Steensgaard, Andreas Vegge, Leona Plum-Mörschel
{"title":"2型糖尿病患者每周一次服用伊科达克胰岛素和赛马鲁肽固定比例复方制剂的药代动力学特性与单独服用每种成分的药代动力学特性的比较。","authors":"Lisbet Westergaard, Lene Alifrangis, Stephen T Buckley, Hans Veit Coester, Thomas Klitgaard, Niels R Kristensen, Erica Nishimura, Lea Nørgreen, Thaís M P Rocha, Dorte B Steensgaard, Andreas Vegge, Leona Plum-Mörschel","doi":"10.1007/s40261-024-01405-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.0-8.5%) received single subcutaneous injections of IcoSema (175 U icodec, 0.5 mg semaglutide), icodec (175 U) or semaglutide (0.5 mg) with 6-9 weeks' washout. Pharmacokinetic blood samples were drawn up to 840 h post-dose.</p><p><strong>Results: </strong>Icodec pharmacokinetics were unaffected by combining icodec with semaglutide. The 90% confidence interval (CI) of IcoSema/icodec was within 0.80-1.25 for total exposure (area under the curve from zero to last quantifiable observation; AUC<sub>0-t</sub>: ratio [90% CI] 1.06 [1.01; 1.12]) and maximum concentration (C<sub>max</sub>): 1.12 [1.06; 1.18]. Semaglutide AUC<sub>0-t</sub> was also unaffected by combination with icodec (IcoSema/semaglutide 1.11 [1.05; 1.17]). However, semaglutide C<sub>max</sub> was higher for IcoSema versus semaglutide alone (IcoSema/semaglutide 1.99 [1.84; 2.15]) and occurred earlier for IcoSema (12 versus 84 h). Results of in vitro albumin binding studies and animal pharmacokinetic studies supported that the change in semaglutide absorption pharmacokinetics in IcoSema is owing to competition for albumin binding locally at the injection site with icodec outcompeting semaglutide. IcoSema, icodec and semaglutide were well-tolerated, although more gastrointestinal related adverse events occurred with IcoSema versus icodec or semaglutide alone.</p><p><strong>Conclusion: </strong>The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema.</p><p><strong>Clinical trial: </strong>ClinicalTrials.gov identifier: NCT03789578.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"849-861"},"PeriodicalIF":2.9000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564230/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetic Properties of a Once-Weekly Fixed-Ratio Combination of Insulin Icodec and Semaglutide Compared with Separate Administration of Each Component in Individuals with Type 2 Diabetes Mellitus.\",\"authors\":\"Lisbet Westergaard, Lene Alifrangis, Stephen T Buckley, Hans Veit Coester, Thomas Klitgaard, Niels R Kristensen, Erica Nishimura, Lea Nørgreen, Thaís M P Rocha, Dorte B Steensgaard, Andreas Vegge, Leona Plum-Mörschel\",\"doi\":\"10.1007/s40261-024-01405-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.0-8.5%) received single subcutaneous injections of IcoSema (175 U icodec, 0.5 mg semaglutide), icodec (175 U) or semaglutide (0.5 mg) with 6-9 weeks' washout. Pharmacokinetic blood samples were drawn up to 840 h post-dose.</p><p><strong>Results: </strong>Icodec pharmacokinetics were unaffected by combining icodec with semaglutide. The 90% confidence interval (CI) of IcoSema/icodec was within 0.80-1.25 for total exposure (area under the curve from zero to last quantifiable observation; AUC<sub>0-t</sub>: ratio [90% CI] 1.06 [1.01; 1.12]) and maximum concentration (C<sub>max</sub>): 1.12 [1.06; 1.18]. Semaglutide AUC<sub>0-t</sub> was also unaffected by combination with icodec (IcoSema/semaglutide 1.11 [1.05; 1.17]). However, semaglutide C<sub>max</sub> was higher for IcoSema versus semaglutide alone (IcoSema/semaglutide 1.99 [1.84; 2.15]) and occurred earlier for IcoSema (12 versus 84 h). Results of in vitro albumin binding studies and animal pharmacokinetic studies supported that the change in semaglutide absorption pharmacokinetics in IcoSema is owing to competition for albumin binding locally at the injection site with icodec outcompeting semaglutide. IcoSema, icodec and semaglutide were well-tolerated, although more gastrointestinal related adverse events occurred with IcoSema versus icodec or semaglutide alone.</p><p><strong>Conclusion: </strong>The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema.</p><p><strong>Clinical trial: </strong>ClinicalTrials.gov identifier: NCT03789578.</p>\",\"PeriodicalId\":10402,\"journal\":{\"name\":\"Clinical Drug Investigation\",\"volume\":\" \",\"pages\":\"849-861\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564230/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Drug Investigation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40261-024-01405-8\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/3 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Drug Investigation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40261-024-01405-8","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/3 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Pharmacokinetic Properties of a Once-Weekly Fixed-Ratio Combination of Insulin Icodec and Semaglutide Compared with Separate Administration of Each Component in Individuals with Type 2 Diabetes Mellitus.
Background and objective: IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM).
Methods: In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.0-8.5%) received single subcutaneous injections of IcoSema (175 U icodec, 0.5 mg semaglutide), icodec (175 U) or semaglutide (0.5 mg) with 6-9 weeks' washout. Pharmacokinetic blood samples were drawn up to 840 h post-dose.
Results: Icodec pharmacokinetics were unaffected by combining icodec with semaglutide. The 90% confidence interval (CI) of IcoSema/icodec was within 0.80-1.25 for total exposure (area under the curve from zero to last quantifiable observation; AUC0-t: ratio [90% CI] 1.06 [1.01; 1.12]) and maximum concentration (Cmax): 1.12 [1.06; 1.18]. Semaglutide AUC0-t was also unaffected by combination with icodec (IcoSema/semaglutide 1.11 [1.05; 1.17]). However, semaglutide Cmax was higher for IcoSema versus semaglutide alone (IcoSema/semaglutide 1.99 [1.84; 2.15]) and occurred earlier for IcoSema (12 versus 84 h). Results of in vitro albumin binding studies and animal pharmacokinetic studies supported that the change in semaglutide absorption pharmacokinetics in IcoSema is owing to competition for albumin binding locally at the injection site with icodec outcompeting semaglutide. IcoSema, icodec and semaglutide were well-tolerated, although more gastrointestinal related adverse events occurred with IcoSema versus icodec or semaglutide alone.
Conclusion: The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema.
期刊介绍：
Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes:
-Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs.
-Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice.
-Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed.
-Studies focusing on the application of drug delivery technology in healthcare.
-Short communications and case study reports that meet the above criteria will also be considered.
Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Clinical Drug Investigation may be accompanied by plain language summaries to assist readers who have some knowledge, but non in-depth expertise in, the area to understand important medical advances.
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