Horizon Therapeutics plc, 150 S. Saunders Rd, Lake Forest, IL, 60045, USA.
Shanghai Qiangshi Information Technology Co., Ltd, Shanghai, China.
Clin Pharmacokinet. 2021 Aug;60(8):1029-1040. doi: 10.1007/s40262-021-01003-3. Epub 2021 Mar 26.
Thyroid eye disease (TED) is characterized by inflammation/expansion of orbital tissues, proptosis, and diplopia. Teprotumumab is the first US Food and Drug Administration-approved therapy for TED, administered as an initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks for an additional seven infusions. The objective of this article is to discuss the pharmacokinetics and exposure-response profile for teprotumumab in patients with TED.
A population pharmacokinetic analysis was performed to characterize pharmacokinetics and select dosing in patients with TED. Exposure-response was evaluated for efficacy (proptosis response, clinical activity score categorical response, and diplopia response) and safety (hyperglycemia, muscle spasms, and hearing impairment) parameters.
Teprotumumab pharmacokinetics was linear in patients with TED, with low systemic clearance (0.334 L/day), low volume of distribution (3.9 and 4.2 L for the central and peripheral compartment, respectively), and a long elimination half-life (19.9 days). The approved dosing regimen provided > 20 µg/mL for > 90% insulin-like growth factor 1 receptor saturation throughout the dosing interval. Model-predicted mean (± standard deviation) steady-state area under the concentration-time curve, peak, and trough concentrations in patients with TED were 131 (± 30.9) mg∙h/mL, 643 (± 130) µg/mL, and 157 (± 50.6) µg/mL, respectively. Female patients had a 15% higher steady-state peak concentration but a similar steady-state area under the concentration-time curve vs male patients. No other covariates affected teprotumumab pharmacokinetics. No meaningful correlations between teprotumumab exposures and efficacy or safety parameters were observed.
Teprotumumab pharmacokinetics was well characterized in patients with TED, and generally consistent with other IgG1 antibodies. Efficacy was consistent across the exposure range with a well-tolerated safety profile supporting the current dose regimen for patients with TED.
甲状腺眼病（TED）的特征为眼眶组织炎症/扩张、眼球突出和复视。特普罗斯单抗是首个获得美国食品和药物管理局批准用于 TED 的治疗药物，初始静脉输注剂量为 10 mg/kg，随后每 3 周输注 20 mg/kg，共输注 7 次。本文旨在讨论 TED 患者中特普罗斯单抗的药代动力学和暴露-反应特征。
进行了一项群体药代动力学分析，以确定 TED 患者的药代动力学特征并选择剂量。评估了疗效（眼球突出反应、临床活动评分分类反应和复视反应）和安全性（高血糖、肌肉痉挛和听力损伤）参数的暴露-反应关系。
TED 患者的特普罗斯单抗药代动力学呈线性，系统清除率低（0.334 L/天），分布容积低（中央和外周隔室分别为 3.9 和 4.2 L），消除半衰期长（19.9 天）。批准的给药方案在整个给药间隔内为胰岛素样生长因子 1 受体提供了>20 µg/mL 的覆盖率，>90%。TED 患者模型预测的稳态平均（±标准偏差）浓度-时间曲线下面积、峰浓度和谷浓度分别为 131（±30.9）mg·h/mL、643（±130）µg/mL 和 157（±50.6）µg/mL。女性患者的稳态峰浓度比男性患者高 15%，但稳态浓度-时间曲线下面积相似。没有其他协变量影响特普罗斯单抗的药代动力学。未观察到特普罗斯单抗暴露与疗效或安全性参数之间存在有意义的相关性。
TED 患者的特普罗斯单抗药代动力学特征良好，与其他 IgG1 抗体基本一致。在可耐受的安全性特征下，疗效与暴露范围一致，支持目前 TED 患者的剂量方案。
