DDMoRe Model Repository

Short description:

This is the myelosuppression model (first published by Friberg et al. 2002) for docetaxel, including covariates identified by Kloft et al., 2006. The variability related to the gamma parameter was set to 0, in contrast to the original publication.

Format:	Original code
Related Publication:	Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs. Kloft C, Wallin J, Henningsson A, Chatelut E, Karlsson MO Clinical cancer research : an official journal of the American Association for Cancer Research, 9/2006, Volume 12, Issue 18, pages: 5481-5490 Affiliation: Department of Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin, Germany. ckloft@zedat.fu-berlin.de Abstract: PURPOSE: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs. EXPERIMENTAL DESIGN: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made. RESULTS: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha1-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction. CONCLUSIONS: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.
Contributors:	Ida Netterberg

Context of model development:	Dose & Schedule Selection and Label Recommendation;
Discrepancy between implemented model and original publication:	No variability related to the gamma parameter;
Model compliance with original publication:	No;
Model implementation requiring submitter’s additional knowledge:	No;
Modelling context description:	This model was used to simulate daily measurements of ANC, which was subsequently used to predict the ANC with varying amount of data available for making the predictions. Also the precision of predicting time to baseline recovery, time to nadir and the nadir ANC value, was evaluated ;
Modelling task in scope:	simulation;
Nature of research:	Clinical research & Therapeutic use;
Therapeutic/disease area:	Oncology;

Validation Status:	Annotations are correct.
Certification Comment:	This model is not certified.

DDMODEL00000224: Kloft_2006_myelosuppression_docetaxel

Revisions