Sym004 is an equimolar mixture of two monoclonal antibodies, futuximab and modotuximab, which non-competitively block the epidermal growth factor receptor (EGFR). Sym004 has been clinically tested for treatment of solid tumors. The present work characterizes the non-linear pharmacokinetics (PK) of Sym004 and its constituent antibodies and investigates two types of covariate models for interpreting the interindividual variability of Sym004 exposure. Sym004 serum concentration data from 330 cancer patients participating in four Phase 1 and 2 trials (n = 247 metastatic colorectal cancer, n = 87 various types advanced solid tumors) were pooled for non-linear mixed effects modeling. Dose regimens of 0.4–18 mg/kg Sym004 dosed by i.v. infusion weekly or every 2nd week were explored. The PK profiles for futuximab and modotuximab were parallel, and the parameter values for their population PK models were similar. The PK of Sym004 using the sum of the serum concentrations of futuximab and modotuximab was well captured by a 2-compartment model with parallel linear and saturable, Michaelis–Menten-type elimination. The full covariate model including all plausible covariates included in a single step showed no impact on Sym004 exposure of age, Asian race, renal and hepatic function, tumor type and previous anti-EGFR treatments. The reduced covariate model contained statistically and potentially clinically significant influences of body weight, albumin, sex and baseline tumor size. Population PK modeling and covariate analysis of Sym004 were feasible using the sum of the serum concentrations of the two constituent antibodies. Full and reduced covariate models provided insights into which covariates may be clinically relevant for dose modifications and thus may need further exploration.

中文翻译：

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Sym004（一种针对表皮生长因子受体的抗体混合物）在患有转移性结直肠癌和其他实体瘤的受试者中的群体药代动力学和协变量分析。

Sym004是两种单抗的同等混合物，分别为futuximab和modotuximab，它们非竞争性地阻断了表皮生长因子受体（EGFR）。Sym004已通过临床测试，可用于治疗实体瘤。本工作表征了Sym004及其组成抗体的非线性药代动力学（PK），并研究了两种类型的协变量模型来解释Sym004暴露的个体间差异。收集来自330名癌症患者的Sym004血清浓度数据，这些患者参加了4个1期和2期试验（n = 247转移性结直肠癌，n = 87各种类型的晚期实体瘤），用于非线性混合效应模型。研究了每周或每2周静脉输注0.4-18 mg / kg Sym004的剂量方案。Futuximab和Modotuximab的PK曲线是平行的，并且其人口PK模型的参数值相似。使用具有平行线性和饱和Michaelis-Menten型消除作用的2室模型，可以很好地捕获使用Futuximab和modotuximab血清浓度之和的Sym004的PK。完整的协变量模型包括一个步骤中包含的所有可能的协变量，对年龄，亚洲种族，肾和肝功能，肿瘤类型和以前的抗EGFR治疗的Sym004暴露无影响。简化的协变量模型包含体重，白蛋白，性别和基线肿瘤大小的统计学上和潜在的临床上显着影响。使用两种组成抗体的血清浓度之和，对Sym004进行群体PK建模和协变量分析是可行的。