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Background and Objective <p>Current body surface area (BSA)-based dosing of liposomal paclitaxel (L-PTX) fails to account for substantial interpatient variability in drug exposure, leading to inconsistent therapeutic outcomes. This study investigated the relationships between L-PTX pharmacokinetic exposure (quantified as time above threshold concentration [Tc<sub>&gt;0.05</sub>]), CYP2C8 metabolic activity, and clinical outcomes in gynecological oncology patients receiving platinum-based combination therapy with L-PTX.</p> Materials and Methods <p>We conducted a study of 85 patients with gynecological tumors receiving platinum-based combination therapy with L-PTX (September 2020–January 2023). Plasma concentrations of paclitaxel and its metabolite 6α-hydrpaclitaxel (6α-OHP) were measured 20–22 h post-infusion using validated ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) methods. Tc<sub>&gt;0.05</sub> and CYP2C8 activity (6α-OHP/PTX ratio) were calculated. Clinical outcomes were assessed on the basis of progression-free status, with disease recurrence or progression recorded during follow-up. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) grading.</p> Results <p>L-PTX Tc<sub>&gt;0.05</sub> was normally distributed within the range of 13.49–41.30 h, with up to a threefold difference among patients. CYP2C8 metabolic enzyme activity showed a non-normal distribution, ranging from 0.00469 to 0.08830, with up to an 18-fold difference. Correlation analysis revealed that L-PTX Tc<sub>&gt;0.05</sub> and CYP2C8 metabolic enzyme activity were significantly correlated with clinical efficacy and neutropenia. The results suggest a potential therapeutic range for L-PTX Tc<sub>&gt;0.05</sub> in patients with gynecological tumors of approximately 21–29 h.</p> Conclusions <p>BSA-based L-PTX dosing inadequately addresses pharmacokinetic variability. We demonstrate that Tc<sub>&gt;0.05</sub> and CYP2C8 activity significantly influence treatment outcomes and toxicity, supporting the need for personalized dosing strategies. The suggested target range (approximately 21–29 h) warrants further validation in prospective clinical trials before it can be considered for clinical application.</p>

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Personalizing Liposomal Paclitaxel in Platinum-Based Combination Therapy for Gynecologic Cancers: Defining a Therapeutic Window Based on Tc>0.05 and CYP2C8 Metabolic Capacity

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Shuai Jiang,
  • Yao Yao,
  • Dongqing Gao,
  • Jiahui Liu,
  • Tingting Ding,
  • Yuexin Li,
  • Mei Dong

摘要

Background and Objective

Current body surface area (BSA)-based dosing of liposomal paclitaxel (L-PTX) fails to account for substantial interpatient variability in drug exposure, leading to inconsistent therapeutic outcomes. This study investigated the relationships between L-PTX pharmacokinetic exposure (quantified as time above threshold concentration [Tc>0.05]), CYP2C8 metabolic activity, and clinical outcomes in gynecological oncology patients receiving platinum-based combination therapy with L-PTX.

Materials and Methods

We conducted a study of 85 patients with gynecological tumors receiving platinum-based combination therapy with L-PTX (September 2020–January 2023). Plasma concentrations of paclitaxel and its metabolite 6α-hydrpaclitaxel (6α-OHP) were measured 20–22 h post-infusion using validated ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) methods. Tc>0.05 and CYP2C8 activity (6α-OHP/PTX ratio) were calculated. Clinical outcomes were assessed on the basis of progression-free status, with disease recurrence or progression recorded during follow-up. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) grading.

Results

L-PTX Tc>0.05 was normally distributed within the range of 13.49–41.30 h, with up to a threefold difference among patients. CYP2C8 metabolic enzyme activity showed a non-normal distribution, ranging from 0.00469 to 0.08830, with up to an 18-fold difference. Correlation analysis revealed that L-PTX Tc>0.05 and CYP2C8 metabolic enzyme activity were significantly correlated with clinical efficacy and neutropenia. The results suggest a potential therapeutic range for L-PTX Tc>0.05 in patients with gynecological tumors of approximately 21–29 h.

Conclusions

BSA-based L-PTX dosing inadequately addresses pharmacokinetic variability. We demonstrate that Tc>0.05 and CYP2C8 activity significantly influence treatment outcomes and toxicity, supporting the need for personalized dosing strategies. The suggested target range (approximately 21–29 h) warrants further validation in prospective clinical trials before it can be considered for clinical application.