Hanauer Stephen B, Torres Esther A, Aragon-Han Patricia, Chapman Jonathon C, Swaminath Arun C, Arai Ronen, Butnariu Mandalina, Lee Thomas C, Rabizadeh Shervin, Check Morgan, Barrett Terrence A, Hashash Jana G, Meister Thomas, Yen Eugene F, Kinnucan Jami, Stein Daniel J, Ziring David, Shaposhnikov Rimma, Sinh Preetika, Qazi Taha M, Yarur Andres J, Monzur Farah, Dervieux Thierry, Abraham Bincy P
School of Medicine, Northwestern University Feinberg, Chicago, IL 60611, USA.
Department of Medicine, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan 00936, Puerto Rico.
Pharmaceutics. 2025 Mar 27;17(4):428. doi: 10.3390/pharmaceutics17040428.
: This study aimed to establish the clinical utility of a therapeutic drug monitoring (TDM)-supported, model-informed precision dosing (MIPD) approach (precision-guided dosing [PGD]) by assessing the impact of pharmacokinetic (clearance [CL]) and clinical laboratory parameters on adalimumab (ADA) dosage adjustments during maintenance therapy for inflammatory bowel disease (IBD). : In the EMPOWER study, blood was collected at any time post-ADA injection. Pharmacokinetic (PK) testing was conducted in an accredited lab. Inputs for the PGD test included ADA concentrations, antibodies to ADA, albumin levels, and the current dosing regimen. CL was calculated using nonlinear mixed-effect models. Results were reported to health care providers (HCPs) within 3 days. HCPs' treatment decisions were recorded and classified as treatment reduction, continuation, intensification, or ADA discontinuation. The physician global assessment (PGA) of disease activity was collected. Relationships between drug concentrations, CL, disease activity, and physician decision-making were assessed using logistic regression. : A total of 213 cases were assessed by 21 HCPs. ADA treatment was intensified in 24% and discontinued in 13% of cases. An ADA concentration ≤ 10 μg/mL was associated with a 23.7-fold and 3.0-fold higher likelihood of therapy intensification and PGA > 0, respectively, compared to concentrations > 10 μg/mL. An ADA concentration < 5 μg/mL was associated with a 3.3-fold higher likelihood of treatment discontinuation. CL ≥ 0.318 L/day was associated with a 10.4-fold higher likelihood of therapy intensification. Higher CL (>0.8 L/day) was associated with a 3.5-fold and 4.2-fold higher likelihood of treatment discontinuation and PGA > 0, respectively. : PGD enables earlier and precise optimization of ADA dosing by predicting trough levels at any time during the therapy cycle. Optimized dosing to achieve target ADA concentrations and low clearance is crucial to mitigate therapy discontinuation and active disease in IBD patients.
本研究旨在通过评估药代动力学（清除率[CL]）和临床实验室参数对炎症性肠病（IBD）维持治疗期间阿达木单抗（ADA）剂量调整的影响，建立一种由治疗药物监测（TDM）支持的、模型指导的精准给药（MIPD）方法（精准指导给药[PGD]）的临床实用性。：在EMPOWER研究中，在ADA注射后的任何时间采集血液。药代动力学（PK）检测在一家经认可的实验室进行。PGD检测的输入参数包括ADA浓度、ADA抗体、白蛋白水平和当前给药方案。使用非线性混合效应模型计算CL。结果在3天内报告给医疗保健提供者（HCPs）。记录HCPs的治疗决策并分类为治疗减量、继续、强化或停用ADA。收集疾病活动的医生整体评估（PGA）。使用逻辑回归评估药物浓度、CL、疾病活动和医生决策之间的关系。：21名HCPs共评估了213例病例。24%的病例中ADA治疗得到强化，13%的病例中ADA治疗被停用。与浓度>10μg/mL相比，ADA浓度≤10μg/mL分别与治疗强化和PGA>0的可能性高23.7倍和3.0倍相关。ADA浓度<5μg/mL与治疗停用的可能性高3.3倍相关。CL≥0.318L/天与治疗强化的可能性高10.4倍相关。较高的CL（>0.8L/天）分别与治疗停用和PGA>0的可能性高3.5倍和4.2倍相关。：PGD通过预测治疗周期内任何时间的谷浓度，能够更早、更精确地优化ADA给药。优化给药以达到目标ADA浓度和低清除率对于减轻IBD患者的治疗停用和活动性疾病至关重要。
