Population pharmacokinetic modelling of prednisolone in systemic lupus erythematosus patients: Analysis of exposure and disease activity.

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Naïm Bouazza, Michaela Semeraro, Gabrielle Lui, Léo Froelicher-Bournaud, Laure Choupeaux, Jean-Marc Treluyer, Sihem Benaboud, Joelle Terzic, Eric Hachulla, Philippe Remy, Jérôme Harambat, Alexandre Karras, Caroline Rousset-Rouviere, Anne Jolivot, Zahir Amoura, Eric Daugas, Aurélie Hummel, Rémi Salomon, Jean-Christophe Lega, Stéphane Decramer, Alexandre Belot, Delphine Gobert, Nathalie Costedoat-Chalumeau, Stanislas Faguer, Isabelle Melki, Noémie Jourde-Chiche, Brigitte Bader-Meunier
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引用次数: 0

Abstract

Aims: Prednisone is a widely used glucocorticoid in the treatment of lupus, although its dosing is often determined empirically. Prednisolone, the active metabolite of prednisone, is found in its free form in the serum. The goal of this study was to develop a population pharmacokinetic model in patients with systemic lupus erythematosus (SLE) to forecast free prednisolone concentrations and its association with disease activity.

Methods: A total of 66 active SLE patients (adults and children) were included, and followed up prospectively (242 observations available). Plasma prednisolone concentrations were assessed using liquid chromatography-mass spectrometry, and the data were analysed using Monolix software. The pharmacokinetic model was a one-compartment open model with absorption lag time representing the delay for both absorption and metabolism from inactive (prednisone) to active form (prednisolone). This model predicted free concentrations, which were then used to calculate total concentrations based on established binding constants.

Results: Free prednisolone clearance (CLu/F) and volume of distribution (Vu/F) were scaled allometrically to body weight. The typical population estimates (95% confidence interval) were 54 (48-62) L/h/70 kg and 235 (203-274) L/70 kg, respectively. Additionally, the bioavailability parameter was found to decrease non-linearly with the dose. Prednisolone cumulative exposure was not different between patients who responded at 3 months and those who did not.

Conclusions: Robust pharmacokinetic targets are not yet clearly defined regarding toxicity or efficacy and are warranted in order to make a valuable contribution to prednisolone therapeutic drug monitoring in the context of SLE.

泼尼松龙在系统性红斑狼疮患者中的群体药代动力学模型:暴露和疾病活动性分析。
目的:强的松是一种广泛用于治疗狼疮的糖皮质激素,尽管其剂量通常是经验决定的。强的松龙是强的松的活性代谢物,在血清中以游离形式存在。本研究的目的是建立系统性红斑狼疮(SLE)患者的群体药代动力学模型,以预测游离强的松龙浓度及其与疾病活动性的关系。方法:共纳入66例活动性SLE患者(成人和儿童),并进行前瞻性随访(242例观察)。使用液相色谱-质谱法评估血浆强的松龙浓度,并使用Monolix软件对数据进行分析。药代动力学模型为单室开放模型,吸收滞后时间表示从非活性形式(强的松)到活性形式(强的松)的吸收和代谢的延迟。该模型预测了游离浓度,然后根据已建立的结合常数计算总浓度。结果:游离强的松龙清除率(CLu/F)和分布体积(Vu/F)与体重呈异速比例。典型种群估计(95%置信区间)分别为54 (48-62)L/h/70 kg和235 (203-274)L/70 kg。此外,生物利用度随剂量呈非线性下降。强的松龙累积暴露在3个月时有反应的患者和没有反应的患者之间没有差异。结论:强有力的药代动力学靶点在毒性或有效性方面尚未明确定义,为了在SLE背景下对泼尼松龙治疗药物监测做出有价值的贡献,是有必要的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.30
自引率
8.80%
发文量
419
审稿时长
1 months
期刊介绍: Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.
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