Pharmacy Department, Division of Medicines, Hospital Clinic Barcelona, Universitat de Barcelona, Spain.
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
Br J Clin Pharmacol. 2018 Apr;84(4):716-725. doi: 10.1111/bcp.13500. Epub 2018 Feb 7.
Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach.
Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 10 μg h ml .
A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 l h , 4.83 l, 0.239 mg h and 4.22 μg ml , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category.
Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.
目前，托珠单抗的静脉注射剂量是基于体重的，尽管已经描述了体重与清除率之间的弱相关性。本研究旨在评估当前的给药策略，并通过建模和模拟方法为给药提供科学依据。
从接受每 28 天 4、6 或 8mg 静脉注射托珠单抗治疗的受试者中获得血清浓度和协变量。使用非线性混合效应模型进行群体药代动力学分析。最终模型用于模拟托珠单抗的暴露情况，以评估基于体重或固定剂量的给药策略，目标是治疗 24 周时累积曲线下面积（AUC）超过 100×10μg·h·ml-1。
一个具有平行线性和非线性消除的单室分布模型最能描述浓度-时间数据。清除率、表观分布容积、最大消除率和米氏常数的典型群体平均值分别为 0.0104l·h-1、4.83l、0.239mg·h-1和 4.22μg·ml-1。清除率（17.0%）和分布容积（30.8%）具有个体间变异性。清除率的显著协变量为患者体重和 C 反应蛋白血清水平。体重指数的估计指数为 0.360，证实了托珠单抗清除率与体重的弱相关性。模拟表明，如果使用基于体重的给药方法，体重较低的患者存在剂量不足的风险。然而，固定剂量可以提供更一致的药物暴露，而与体重类别无关。
我们的研究提供了证据支持类风湿关节炎患者静脉注射托珠单抗的固定剂量，因为与当前基于体重的剂量方法相比，它减少了体重类别之间托珠单抗暴露的变异性。
