Docetaxel Skin Exposure and Micronucleation Contributes to Skin Toxicity Caused by CPC634

Simple Summary CPC634 is a nanoparticle entrapping docetaxel that is associated with skin toxicity that resembles conventional docetaxel-related skin toxicity. In this randomised cross-over study, the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634 were compared to unravel the mechanisms behind the cutaneous toxicity. The total docetaxel concentration in the skin was almost four-fold higher after CPC634 administration compared to conventional docetaxel. Both CPC634 and conventional docetaxel administration resulted in anti-mitotic effects in the skin such as micronucleation. Micronucleation can induce an inflammatory reaction, which could lead to skin toxicity. 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(2)). 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%, p < 0.001) higher after CPC634 administration compared to Cd while the released docetaxel concentrations were not statistically different (95%CI: -9% to 63%, p = 0.169). The CPC634 released docetaxel concentration in the skin was positively correlated with plasma concentrations (Pearson's correlation 0.48, p = 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.

Automated summary

CPC634, a nanoparticle entrapping docetaxel, and conventional docetaxel both result in skin toxicity through anti-mitotic effects such as micronucleation, which can lead to inflammatory reactions. The total docetaxel concentration in the skin was significantly higher after CPC634 administration compared to conventional docetaxel, while the released docetaxel concentrations were not statistically different.Histopathological examination revealed increased apoptosis, mitotic cells with nuclear atypia, and micronucleation with an enhanced Ki-67 index for both compounds.