O29 Pharmacometric modelling of free thyroxine dynamics after initiation of antithyroid drug treatment in children with Graves’ disease: a tool for personalized drug dosing in children
O29 Pharmacometric modelling of free thyroxine dynamics after initiation of antithyroid drug treatment in children with Graves’ disease: a tool for personalized drug dosing in children
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O29â 格雷夫斯病儿童开始抗甲状腺药物治疗后游离甲状腺素动态的药理学模型：儿童个性化药物剂量的工具
DOI：
10.1136/archdischild-2019-esdppp.29
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发表时间：
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影响因子：
5.2
通讯作者：
Pfister M
中科院分区：
文献类型：
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作者：
Koch G;Gotta V;Ollagnier C;Konrad D;Flueck C;L’Allemand D;Steigert M;Rohner A;Bachmann F;Schropp J;Szinnai G;Pfister M
背景：甲状腺激素对儿童和青少年的正常生长和青春期至关重要。Graves病（GD）是一种罕见的与甲状腺激素分泌过多相关的自身免疫性疾病，在欧洲发病率为0.5 - 10万儿童（多数为女性）。与成人相比，GD的一线治疗是长期抗甲状腺药物（ATD）治疗，放射性碘消融通常用于青春期后的患者。然而，治疗获得性甲状腺功能亢进症合并ATD是困难的，因为1)儿科患者在年龄、体重和疾病严重程度上差异很大，2)应使用最小的ATD剂量，以避免轻微的副作用（发生在6-35%的患者中），以及罕见的严重副作用，如粒细胞缺乏症和肝功能衰竭。方法回顾性分析来自瑞士多中心队列的纵向临床和实验室数据。应用非线性混合效应模型来描述卡咪唑治疗前3个月游离甲状腺素（FT4）的动态。性别、联合用药如心得安和促甲状腺激素受体抗体作为模型参数的协变量进行检验。FT4的参考范围来源于临床实践中的目标水平（12-22 pmol/L）。结果研究队列包括45名患有GD的儿童，78%为女性，中位年龄12.2岁（IQR=[8.7, 13.6]），共就诊181次。诊断GD时FT4基线为62.3 pmol/L （IQR=[45.7, 86.7]）。所有被测因素均未显示显著的协变量效应。该模型允许对治疗开始时不同GD严重程度、年龄和体重的最佳ATD给药策略（起始和维持剂量）进行个体模拟。个性化剂量的例子将被提出。结论建立的药物计量学模型能够根据ATD剂量/kg/d、年龄、体重和疾病严重程度4个参数预测GD患儿FT4的动态，可用于个性化给药方案，避免过量或不足给药。
BackgroundThyroid hormones are essential for normal growth and puberty in children and adolescents. Graves’ disease (GD) is a rare autoimmune disorder associated with thyroid hormone over-production and occurs in 0.5–2: 100’000 children (mostly females) in Europe. In contrast to adults, first line treatment of GD is long-term antithyroid drug (ATD) therapy, and radioiodine ablation is usually being reserved for patients after puberty. However, treatment of acquired hyperthyroidism with ATD is difficult since 1) paediatric patients differ considerable in age, weight and diseases severity and 2) minimal ATD dose should be used to avoid mild side effects (occurring in 6–35% of patients), and rare severe side effects such as agranulocytosis and liver failure.MethodsLongitudinal clinical and laboratory data from a Swiss multicentre cohort were analysed retrospectively. Non-linear mixed effects modelling was applied to characterize dynamics of free thyroxine (FT4) during the first 3 months of treatment with carbimazole. Sex, co-medications such as propranolol, and thyroid stimulating hormone receptor antibody were tested as covariates on model parameters. Reference range for FT4 was derived from target levels in clinical practice (12–22 pmol/L).ResultsStudy cohort comprised 45 children with GD, 78% females, median age 12.2 years (IQR=[8.7, 13.6])) with a total of 181 visits. FT4 baseline at diagnosis of GD was 62.3 pmol/L (IQR=[45.7, 86.7]). None of the tested factors showed significant covariate effects. The model allows individual simulations of optimal ATD dosing strategies (starting and maintenance dose) for different GD severities, ages and weights at start of therapy. Personalized dosing examples will be presented.ConclusionsDeveloped pharmacometric model is able to predict dynamics of FT4 in children with GD depending on four parameters: ATD dose/kg/d, age, weight and disease severity, and can be applied to personalize dosing regimen to avoid over-or under dosing.