Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
Eur J Pharm Biopharm. 2022 Apr;173:34-44. doi: 10.1016/j.ejpb.2022.02.014. Epub 2022 Feb 25.
Recent reports have highlighted the role of the lymphatic system and its resident immune cells in the development of inflammatory arthritis. Directing therapeutics to the joint-draining lymphatics could improve access to lymphatic-resident pro-inflammatory immune cells, improve local treatment efficacy and enable the administration of lower drug doses to achieve the same or a better effect. Here, we assessed the delivery of disease modifying anti-rheumatic drugs (DMARDs) to the joint-draining lymphatics as a function of therapeutic size and route of administration (intravenous (IV), subcutaneous (SC) and intra-articular (IA) injection). The model drugs included the low molecular weight conventional DMARD methotrexate and the larger biologic DMARDs etanercept and rituximab. Plasma pharmacokinetics, thoracic lymph fluid concentrations and lymph node deposition of the DMARDS were assessed in male Sprague-Dawley rats after IV, IA or SC injection at or near the knee joint. Administration by IA injection resulted in rapid and higher absorption of all drugs into the systemic circulation, compared to SC administration. The large DMARDs etanercept and rituximab were preferentially transported from the IA and SC injection sites via the lymphatics, but a greater percentage of the absorbed dose was recovered in lymph after IA (49-58%) compared to SC administration (17-20%). Methotrexate was almost exclusively transported from the injection site via the blood after IA injection, consistent with its small size which presents minimal barriers to diffusion across the synovium into blood vessels. Importantly, IA but not SC administration resulted in biologic DMARD access to the knee joint-draining iliac lymph fluid and iliac lymph node that is dysfunctional in inflammatory knee arthritis. Overall, IA injection of biologic DMARDs may provide a simple strategy to improve lymph and lymph node access and thus the treatment of inflammatory arthritis.
最近的报告强调了淋巴系统及其驻留免疫细胞在炎症性关节炎发展中的作用。将治疗药物直接输送到关节引流淋巴管，可以改善对淋巴管驻留促炎免疫细胞的药物输送，提高局部治疗效果，并允许使用较低的药物剂量达到相同或更好的效果。在这里，我们评估了作为治疗大小和给药途径（静脉内（IV）、皮下（SC）和关节内（IA）注射）函数的疾病修饰抗风湿药物（DMARDs）向关节引流淋巴管的输送。模型药物包括低分子量常规 DMARD 甲氨蝶呤和较大的生物 DMARD 依那西普和利妥昔单抗。在雄性 Sprague-Dawley 大鼠中，在膝关节附近进行 IV、IA 或 SC 注射后，评估了 DMARDs 的血浆药代动力学、胸淋巴液浓度和淋巴结沉积。与 SC 给药相比，IA 注射可迅速且更多地将所有药物吸收到全身循环中。较大的 DMARD 依那西普和利妥昔单抗优先通过淋巴管从 IA 和 SC 注射部位转运，但 IA（49-58%）给药后吸收剂量的更大百分比在淋巴中回收，而 SC 给药（17-20%）。IA 注射后，甲氨蝶呤几乎完全通过血液从注射部位转运，这与其小尺寸一致，因为其扩散穿过滑膜进入血管的障碍最小。重要的是，IA 给药而不是 SC 给药可使生物 DMARD 进入膝关节引流的髂淋巴结液和在炎症性膝关节关节炎中功能失调的髂淋巴结，这是唯一的方法。总体而言，IA 注射生物 DMARD 可能是一种简单的策略，可以改善淋巴和淋巴结的药物输送，从而治疗炎症性关节炎。
