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.

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY Clinical Drug Investigation Pub Date : 2024-11-03 DOI:10.1007/s40261-024-01405-8
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
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Abstract

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.

Clinical trial: ClinicalTrials.gov identifier: NCT03789578.

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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。
背景和目的IcoSema是每周一次的基础胰岛素icodec和每周一次的胰高血糖素样肽-1受体激动剂semaglutide的皮下固定比例复方制剂。本研究调查了伊科赛马中的icodec和semaglutide在2型糖尿病(T2DM)患者中的药代动力学,以及每种成分单独给药的药代动力学:在一项随机、双盲、三期交叉研究中,31 名 T2DM 患者(18-64 岁,体重 80-120 公斤,糖化血红蛋白 6.0-8.5%)接受了 IcoSema(175 U icodec、0.5 毫克 semaglutide)、icodec(175 U)或 semaglutide(0.5 毫克)的单次皮下注射,并进行了 6-9 周的冲洗。药代动力学血样在服药后840小时内采集:结果:icodec与semaglutide合用不会影响icodec的药代动力学。在总暴露量(从零到最后一次可量化观察的曲线下面积;AUC0-t:比值[90% CI] 1.06 [1.01; 1.12])和最大浓度(Cmax)方面,伊科塞马/伊科代克的 90% 置信区间(CI)在 0.80-1.25 之间:1.12 [1.06; 1.18].塞马鲁肽的AUC0-t也不受与icodec联用的影响(IcoSema/塞马鲁肽:1.11 [1.05; 1.17])。不过,与单独使用塞马鲁肽相比,伊科司马的塞马鲁肽Cmax更高(伊科司马/塞马鲁肽为1.99 [1.84; 2.15]),而且伊科司马的Cmax出现得更早(12小时对84小时)。体外白蛋白结合研究和动物药代动力学研究的结果表明,IcoSema 中塞马鲁肽吸收药代动力学的变化是由于注射部位的白蛋白结合竞争导致的,icodec 优于塞马鲁肽。IcoSema、icodec和semaglutide的耐受性良好,但IcoSema与icodec或单独使用semaglutide相比,发生了更多的胃肠道相关不良事件:结论:在IcoSema中联合使用icodec和semaglutide可提高并提前达到semaglutide的最大浓度,这将为IcoSema的剂量推荐提供指导:临床试验:ClinicalTrials.gov identifier:NCT03789578。
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来源期刊
CiteScore
5.90
自引率
3.10%
发文量
108
审稿时长
6-12 weeks
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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