British journal of clinical pharmacology · 2026
Population pharmacokinetics and pharmacodynamics of intraperitoneal aerosolized nanoparticle albumin-bound paclitaxel (nab-PTX) and metabolites.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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De Sutter Pieter-Jan, Sandra Louis, Van Ovost Judith, Van de Sande Leen, Graversen Martin, Mortensen Michael Bau, Cosyns Sarah, Hoorens Anne, Willaert Wouter, Ceelen Wim, Vermeulen An
Аннотация
AIMS: To characterize the pharmacokinetics (PK), metabolite kinetics and toxicity risk of nanoparticle albumin-bound paclitaxel (Nab-PTX) administered via pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with peritoneal metastasis, using data from a Phase 1 trial.
METHODS: Twenty patients received two to three Nab-PTX PIPACs at doses ranging from 35 to 140 mg/m2 with a four-week dosing interval. A population pharmacokinetic-pharmacodynamic model was developed describing plasma concentrations of paclitaxel and metabolites (6-hydroxy and 3-hydroxy paclitaxel) and neutrophil dynamics. Bioavailability was estimated based on published intravenous data. Logistic regression was used to relate paclitaxel exposure to hepatotoxicity events.
RESULTS: A two-compartment model with zero-order input best describes paclitaxel PK, with an estimated absorption duration of 3.49 h. Bioavailability was estimated at 37.0%. The total apparent volume of distribution of the two-compartment system was 2299 L. The population apparent clearance was 87.3 L/h and was accompanied by moderate variability between subjects and occasions (23.9 and 29.5% CV, respectively). Rate constants of metabolite formation and elimination displayed more extensive variability (52.6%-95.1% CV). Body surface area was incorporated as a covariate on apparent clearance.. Paclitaxel maximum concentrations and total exposure were associated with bilirubin and ALT adverse events, respectively, but not with other hepatotoxicity events. Dosing simulations predicted a low risk (0.8%) of grade 4 neutropenia at the highest investigated dose, with neutrophil nadirs at day 10 and recovery within 3-4 weeks.
CONCLUSIONS: The developed model justifies a 140 mg/m2 Phase 2 dose characterized by slow absorption and tolerable dose-related haematological and hepatic toxicity.
METHODS: Twenty patients received two to three Nab-PTX PIPACs at doses ranging from 35 to 140 mg/m2 with a four-week dosing interval. A population pharmacokinetic-pharmacodynamic model was developed describing plasma concentrations of paclitaxel and metabolites (6-hydroxy and 3-hydroxy paclitaxel) and neutrophil dynamics. Bioavailability was estimated based on published intravenous data. Logistic regression was used to relate paclitaxel exposure to hepatotoxicity events.
RESULTS: A two-compartment model with zero-order input best describes paclitaxel PK, with an estimated absorption duration of 3.49 h. Bioavailability was estimated at 37.0%. The total apparent volume of distribution of the two-compartment system was 2299 L. The population apparent clearance was 87.3 L/h and was accompanied by moderate variability between subjects and occasions (23.9 and 29.5% CV, respectively). Rate constants of metabolite formation and elimination displayed more extensive variability (52.6%-95.1% CV). Body surface area was incorporated as a covariate on apparent clearance.. Paclitaxel maximum concentrations and total exposure were associated with bilirubin and ALT adverse events, respectively, but not with other hepatotoxicity events. Dosing simulations predicted a low risk (0.8%) of grade 4 neutropenia at the highest investigated dose, with neutrophil nadirs at day 10 and recovery within 3-4 weeks.
CONCLUSIONS: The developed model justifies a 140 mg/m2 Phase 2 dose characterized by slow absorption and tolerable dose-related haematological and hepatic toxicity.