J Pharmacokinet Pharmacodyn. 2013 Dec;40(6):701-12. doi: 10.1007/s10928-013-9341-1.
The PK/PD of abatacept, a selective T cell co-stimulation modulator, was examined in rats with collagen-induced arthritis (CIA) using a nonlinear mixed effect modeling approach. Male Lewis rats underwent collagen induction to produce rheumatoid arthritis. Two single-dose groups received either 10 mg/kg intravenous (IV) or 20 mg/kg subcutaneous (SC) abatacept, and one multiple-dose group received one 20 mg/kg SC abatacept dose and four additional 10 mg/kg SC doses. Effects on disease progression (DIS) were measured by paw swelling. Plasma concentrations of abatacept were assayed by enzyme-linked immunosorbent assay. The PK/PD data were sequentially fitted using NONMEM VI. Goodness-of-fit was assessed by objective functions and visual inspection of diagnostic plots. The PK of abatacept followed a two-compartment model with linear elimination. For SC doses, short-term zero-order absorption was assumed with F = 59.2 %. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (k in ) that was inhibited by abatacept. Variation in the PK data could be explained by inter-individual variability in clearance and central compartment volume (V 1 ), while the large variability of the PD data may be the result of paw edema production (k in 0 ) and loss rate constant (k out ). Abatacept has modest effects on paw swelling in CIA rats. The PK/PD profiles were well described by the proposed model and allowed evaluation of inter-individual variability on drug- and DIS-related parameters.
巴利昔单抗（一种选择性 T 细胞共刺激调节剂）的 PK/PD 在胶原诱导关节炎（CIA）大鼠中进行了研究，采用非线性混合效应建模方法。雄性 Lewis 大鼠接受胶原诱导产生类风湿性关节炎。两个单剂量组分别给予 10mg/kg 静脉注射（IV）或 20mg/kg 皮下注射（SC）巴利昔单抗，一个多剂量组给予 1 次 20mg/kg SC 巴利昔单抗剂量和 4 次额外的 10mg/kg SC 剂量。疾病进展（DIS）的影响通过爪肿胀测量。通过酶联免疫吸附试验测定巴利昔单抗的血浆浓度。使用 NONMEM VI 连续拟合 PK/PD 数据。通过目标函数和诊断图的直观检查评估拟合优度。巴利昔单抗的 PK 遵循具有线性消除的两室模型。对于 SC 剂量，假设短期零级吸收，F = 59.2%。疾病进展成分是间接反应模型，爪肿胀产生速率常数（k in ）随时间变化，巴利昔单抗抑制该常数。PK 数据的变异性可以通过清除率和中央室容积（V 1 ）的个体间差异来解释，而 PD 数据的较大变异性可能是爪肿胀产生（k in 0 ）和失活速率常数（k out ）的结果。巴利昔单抗对 CIA 大鼠的爪肿胀有适度的影响。PK/PD 谱由提出的模型很好地描述，并允许评估药物和 DIS 相关参数的个体间变异性。
