European journal of drug metabolism and pharmacokinetics · 2026
Personalizing Liposomal Paclitaxel in Platinum-Based Combination Therapy for Gynecologic Cancers: Defining a Therapeutic Window Based on Tc>0.05 and CYP2C8 Metabolic Capacity.
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Jiang Shuai, Yao Yao, Gao Dongqing, Liu Jiahui, Ding Tingting, Li Yuexin, Dong Mei
Аннотация
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.
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.