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Predicting Paclitaxel Disposition in Humans With Whole-Body Physiologically-Based Pharmacokinetic Modeling.

Qiang Fu | Xinxin Sun | Maryam B Lustburg | Alex Sparreboom | Shuiying Hu
CPT: pharmacometrics & systems pharmacology | 2019

Paclitaxel is a commonly used drug in the treatment of multiple solid tumors, including cancers of the breast, lung, and ovaries. Despite the established exposure-pharmacodynamic relationships for paclitaxel, treatment is associated with wide interindividual pharmacokinetic variability that leads to unpredictability of the agent's clinical activity and toxicity. We hypothesized that physiologically-based modeling approaches could be employed to predict the human pharmacokinetics of paclitaxel following administration of the approved Cremophor-based formulation (Taxol). The model was developed from tissue distribution studies performed in mice and applied to plasma concentration-time data obtained in adult cancer patients receiving Taxol at the approved dose and schedule (175 mg/m2 by a 3-hour intravenous infusion), taking into account interspecies differences in physiological parameters. The final model adequately captured the observed concentrations in patients and allowed prediction of paclitaxel distribution profiles in multiple target organs and can be applied to further refine the chemotherapeutic treatment with a clinically important agent.

Pubmed ID: 31671477

Research resources used in this publication

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R01 CA187176
  • Agency: NCI NIH HHS, United States
    Id: R01 CA215802
  • Agency: NCI NIH HHS, United States
    Id: R01 CA238946

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Phoenix (tool)

RRID:SCR_003163

A second-generation retrovirus producer lines for the generation of helper free ecotropic and amphotropic retroviruses. The lines are based on the 293T cell line (a human embryonic kidney line transformed with adenovirus E1a and carrying a temperature sensitive T antigen co-selected with neomycin). The unique feature of this cell line is that it is highly transfectable with either calcium phosphate mediated transfection or lipid-based transfection protocols-- up to 50% or higher of cells can be transiently transfected. The lines were created by placing into 293T cells constructs capable of producing gag-pol, and envelope protein for ecotropic and amphotropic viruses. The lines offered advantages over previous stable systems in that virus can be produced in just a few days. Academic and non-profit laboratories may obtain the Phoenix cells from either Allele Biotechnology or the National Gene Vector Bank. The vectors may be obtained from Addgene. They are no longer distributing these reagents from the lab.

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WinNonlin (tool)

RRID:SCR_024504

Software to automate repetitive analysis steps and is widely considered the industry standard for NCA, TK, and PK/PD modeling. Used as non-compartmental analysis (NCA), pharmacokinetic/pharmacodynamic (PK/PD), and toxicokinetic (TK) modeling tool.

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