Atrafi Florence, van Eerden Ruben A G, Koolen Stijn L W, de Bruijn Peter, Rijcken Cristianne J F, Hanssen Rob, Eskens Ferry A L M, Lolkema Martijn P, Oomen-de Hoop Esther, Damman Jeffrey, Mathijssen Ron H J
Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands.
Department of Hospital Pharmacy, Erasmus MC, 3015 GD Rotterdam, The Netherlands.
Cancers (Basel). 2021 Jul 26;13(15):3741. doi: 10.3390/cancers13153741.
Docetaxel entrapped nanoparticle CPC634 is associated with dose-related skin toxicity that resembles conventional docetaxel (Cd)-related skin toxicity. This study compared the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634. In this randomised cross-over study, patients with solid tumours received one cycle of CPC634 and Cd (both at 75 mg/m). Skin biopsies were taken at baseline and at day 8 of both cycles. Released and total docetaxel (released docetaxel plus entrapped docetaxel) concentrations and histopathological changes in the skin biopsies were evaluated. Twenty patients underwent paired skin biopsies for pharmacokinetic analysis and 10 patients had biopsies available for histopathological assessment. The total skin docetaxel concentration was 369% (95%CI: 229% to 569%, < 0.001) higher after CPC634 administration compared to Cd while the released docetaxel concentrations were not statistically different (95%CI: -9% to 63%, = 0.169). The CPC634 released docetaxel concentration in the skin was positively correlated with plasma concentrations (Pearson's correlation 0.48, = 0.03). Histopathological examination revealed increased apoptosis, mitotic cells with nuclear atypia, and micronucleation with an enhanced Ki-67 index for both compounds. In conclusion, both CPC634 and Cd treatment result in docetaxel exposure in the skin causing cutaneous anti-mitotic effects such as micronucleation, which could induce an inflammatory reaction leading to skin toxicity.
多西他赛包裹纳米颗粒CPC634与剂量相关的皮肤毒性有关，这种毒性类似于传统多西他赛（Cd）相关的皮肤毒性。本研究比较了多西他赛和CPC634的皮肤药代动力学和药效学。在这项随机交叉研究中，实体瘤患者接受一个周期的CPC634和Cd治疗（均为75mg/m）。在两个周期的基线和第8天进行皮肤活检。评估皮肤活检中释放的和总的多西他赛（释放的多西他赛加包裹的多西他赛）浓度以及组织病理学变化。20名患者接受配对皮肤活检进行药代动力学分析，10名患者的活检可用于组织病理学评估。与Cd相比，CPC634给药后皮肤中总的多西他赛浓度高369%（95%CI：229%至569%，<0.001），而释放的多西他赛浓度无统计学差异（95%CI：-9%至63%，=0.169）。皮肤中CPC634释放的多西他赛浓度与血浆浓度呈正相关（Pearson相关系数0.48，=0.03）。组织病理学检查显示，两种化合物均有凋亡增加、有核异型性的有丝分裂细胞和微核形成，且Ki-67指数增强。总之，CPC634和Cd治疗均导致皮肤中多西他赛暴露，引起皮肤抗有丝分裂作用，如微核形成，这可能诱发炎症反应导致皮肤毒性。
