a SMARTc Unit, Pharmacokinetics Laboratory, Inserm UMR U1068 Centre de Recherche en Cancérologie de Marseille , Aix-Marseille Universite , Marseille , France.
Expert Rev Clin Pharmacol. 2018 Jun;11(6):599-610. doi: 10.1080/17512433.2018.1477586. Epub 2018 May 24.
The Pharmacokinetics/pharmacodynamics (PK/PD) relationships with cytotoxics are usually based on a steepening concentration-effect relationship; the greater the drug amount, the greater the effect. The Maximum Tolerated Dose paradigm, finding the balance between efficacy, while keeping toxicities at their manageable level, has been the rule of thumb for the last 50-years. Developing nanodrugs is an appealing strategy to help broaden this therapeutic window. The fact that efficacy and toxicity with cytotoxics are intricately linked is primarily due to the complete lack of specificity toward the tumor tissue during their distribution phase. Because nanoparticles are expected to better target tumor tissue while sparing healthy cells, accumulating large amounts of cytotoxics in tumors could be achieved in a safer way. Areas covered: This review aims at presenting how nanodrugs present unique features leading to reconsidering PK/PD relationships of anticancer agents. Expert commentary: The constant interplay between carrier PK, interactions with cancer cells, payload release, payload PK, target expression and target engagement, makes picturing the exact PK/PD relationships of nanodrugs particularly challenging. However, those improved PK/PD relationships now make the once contradictory higher efficacy and lower toxicities requirement an achievable goal in cancer patients.
药物动力学/药效学（PK/PD）关系与细胞毒素通常基于浓度效应关系的陡峭化；药物剂量越大，效果越大。在过去的 50 年中，找到疗效与毒性之间的平衡，同时将毒性控制在可管理的水平一直是经验法则。开发纳米药物是一种有吸引力的策略，可以帮助拓宽这一治疗窗口。细胞毒素的疗效和毒性紧密相关的主要原因是在其分布阶段对肿瘤组织完全缺乏特异性。由于纳米颗粒有望更好地靶向肿瘤组织，同时保护健康细胞，因此可以更安全地在肿瘤中积累大量细胞毒素。涵盖领域：本篇综述旨在介绍纳米药物如何呈现独特的特征，从而重新考虑抗癌药物的 PK/PD 关系。专家评论：载体 PK、与癌细胞相互作用、有效载荷释放、有效载荷 PK、靶表达和靶结合之间的持续相互作用，使得描绘纳米药物的确切 PK/PD 关系特别具有挑战性。然而，这些改善的 PK/PD 关系现在使曾经相互矛盾的更高疗效和更低毒性要求成为癌症患者的可行目标。
