Pharmetheus AB, Uppsala, Sweden.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
CPT Pharmacometrics Syst Pharmacol. 2023 Feb;12(2):154-167. doi: 10.1002/psp4.12885. Epub 2022 Dec 25.
Dr. Reddy's Laboratories rituximab (DRL_RI; Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI-01-002 (Clinical Trials Registry - India/2012/11/003129), comparing DRL_RI to the reference medicinal product (RMP) MabThera® (Roche, Grenzach-Wyhlen, Germany), demonstrated pharmacokinetic (PK) equivalence and showed comparable pharmacodynamic, efficacy, safety, and immunogenicity profiles. We used data from the same study to perform population PK and PK-pharmacodynamic analyses: first exploring possible factors influencing the PK similarity assessment between products and then performing simulations to investigate the impact of tumor size on rituximab PK. Nonlinear mixed-effects models for PK, tumor size, tumor size-PK, and tumor response were developed independently. The final PK model included drug product as a dose-scaling parameter and predicted a 6.75% higher dose reaching the system in RMP-treated patients. However, when tumor size was included in the tumor size-PK model, the drug product effect was no longer observed. The model rather indicated that patients with larger tumor size have higher clearance. Further simulations confirmed that higher baseline tumor size is associated to slightly lower rituximab exposure. Tumor response, described by a continuous-time Markov model, did not differ between drug products. Both had higher effects during the first 20 weeks of treatment. Also, the model described a subpopulation of nonresponders to treatment (42%) with faster transitions to a worse state. The different rituximab exposure initially detected between drug products (6.75%) was shown using PK/PK-pharmacodynamic analysis to be attributed to a tumor size imbalance between treatment groups. PK/PK-pharmacodynamic analyses may contribute to PK similarity assessments.
雷迪博士实验室的利妥昔单抗（DRL_RI；雷迪博士实验室 SA，巴塞尔，瑞士）正在开发中作为一种利妥昔单抗生物类似药。研究 RI-01-002（临床试验注册 - 印度/2012/11/003129），比较 DRL_RI 与参比药品（RMP）美罗华®（罗氏，格伦扎赫-惠伦，德国），显示药代动力学（PK）等效性，并表现出相当的药效学、疗效、安全性和免疫原性特征。我们使用来自同一研究的数据进行群体 PK 和 PK-药效学分析：首先探索可能影响产品间 PK 相似性评估的因素，然后进行模拟研究以调查肿瘤大小对利妥昔单抗 PK 的影响。分别建立了 PK、肿瘤大小、肿瘤大小-PK 和肿瘤反应的非线性混合效应模型。最终 PK 模型包括药物产品作为剂量缩放参数，并预测在 RMP 治疗患者中系统中达到 6.75%更高的剂量。然而，当肿瘤大小被纳入肿瘤大小-PK 模型时，药物产品的作用不再被观察到。该模型表明，肿瘤较大的患者清除率更高。进一步的模拟证实，基线肿瘤较大与利妥昔单抗暴露量略低相关。由连续时间马尔可夫模型描述的肿瘤反应在药物产品之间没有差异。两者在治疗的前 20 周内都有更高的效果。此外，该模型描述了一个对治疗无反应的亚群（42%），其向更差状态的转变更快。最初在药物产品之间检测到的不同利妥昔单抗暴露（6.75%），通过 PK/PK-药效学分析表明，这归因于治疗组之间的肿瘤大小失衡。PK/PK-药效学分析可能有助于 PK 相似性评估。
