Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr 31, 12169, Berlin, Germany.
Graduate Research Training Program, PharMetrX, Berlin, Germany.
Clin Pharmacokinet. 2018 Apr;57(4):515-527. doi: 10.1007/s40262-017-0575-8.
Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency.
Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort or 20 mg of Infacort/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model.
Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline ,15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing <20 kg.
Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing <20 kg. EudraCT number: 2013-000260-28, 2013-000259-42.
在欧洲，目前没有针对 6 岁以下儿童的获批制剂和剂量，因此儿童氢化可的松替代疗法的优化颇具挑战。此外，由于氢化可的松的血浆蛋白结合具有饱和非线性药代动力学特性。因此，开发了一种儿科氢化可的松制剂——具有掩味作用的 Infacort 口服氢化可的松颗粒。本研究的目的是建立一个基于健康成年志愿者研究的群体药代动力学模型，以预测肾上腺皮质功能不全的儿科患者的氢化可的松暴露情况。
在健康志愿者（n=30）中，评估了无地塞米松和有地塞米松时的皮质醇和结合蛋白浓度。在单剂量 0.5、2、5 和 10 mg Infacort 或 20 mg Infacort/氢化可的松片/氢化可的松静脉注射之前和之后，使用地塞米松抑制内源性皮质醇浓度。使用游离和总皮质醇浓度建立了一个血浆蛋白结合模型，并将其依次整合到药代动力学模型中。
皮质醇结合模型中既包含特异性（非线性）结合，也包含非特异性（线性）结合。一个具有饱和吸收和恒定内源性皮质醇基线（Baseline，15.5 nmol/L）的两室处置模型准确地描述了数据。在体重<20 kg 的个体中，对于给定剂量，预测的皮质醇暴露量在较小的体重范围内变化很大。
我们的氢化可的松半机械群体药代动力学模型准确地描述了氢化可的松的复杂药代动力学特性，采用了简化但全面的框架。预测的皮质醇暴露情况表明，对于体重<20 kg 的新生儿和婴儿，准确定义氢化可的松剂量以模拟生理浓度非常重要。EudraCT 编号：2013-000260-28，2013-000259-42。
