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DDMODEL00000186: Friberg_2002_Oncology_Paclitaxel_Mielosupression

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Short description:
Model to describe the time-course of leukocytes (total white blood cell counts) following administration of paclitaxel with linear concentration-effect relationship.
PharmML (0.6.1)
  • Model of chemotherapy-induced myelosuppression with parameter consistency across drugs.
  • Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO
  • Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 12/2002, Volume 20, Issue 24, pages: 4713-4721
  • Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden.
  • PURPOSE: To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs. PATIENTS AND METHODS: Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software. RESULTS: For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs. CONCLUSION: This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.
Zinnia Parra-Guillen
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  • Model owner: Zinnia Parra-Guillen
  • Submitted: Jul 15, 2016 12:14:56 PM
  • Last Modified: Aug 24, 2016 9:03:17 AM
  • Version: 11 public model Download this version
    • Submitted on: Aug 24, 2016 9:03:17 AM
    • Submitted by: Zinnia Parra-Guillen
    • With comment: Edited model metadata online.
  • Version: 7 public model Download this version
    • Submitted on: Jul 15, 2016 12:14:56 PM
    • Submitted by: Zinnia Parra-Guillen
    • With comment: Edited model metadata online.