title: A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model.
abstract: OBJECTIVE
  To improve the predictive capacity of a semi-mechanistic myelosuppression model for neutrophils as the model have shown to over-predict the nadir of neutrophils and, secondly, to develop a model describing the time-course of leukocytes and neutrophils simultaneously.
  
  
  METHODS
  The study included 601 cancer patients treated with a 1 h infusion of docetaxel in monotherapy. A total of 3,549 pairwise observations of leukocytes and neutrophils from one treatment cycle were analyzed simultaneously in NONMEM.
  
  
  RESULTS
  A basic model was developed consisting of a neutrophil and a non-neutrophil model, each with the same structure as the semi-mechanistic myelosuppression model. The leukocytes were modeled as the sum of the predicted neutrophils and non-neutrophils. The model described the time-course of the leukocytes well, but was not able to capture the nadir of the neutrophils. Hence the model was further refined and the included modifications (p < 0.001) in the final model are a sigmoid Emax functions for the drug effect, feedback functions on the cell maturation time in bone-marrow and an optimized number of transit compartments for each of the two cell types.
  
  
  CONCLUSIONS
  A joint semi-mechanistic myelosuppression model describing the time-course of leukocytes and neutrophils following docetaxel administration was developed. The data supported a more complex model compared to the previous model developed by Friberg et al. (2002), and increased the model's capacity to accurately describe the time-course of neutrophils following docetaxel therapy. The combined model also illustrates the differences between the cell types and allows prediction of neutrophil counts from leukocyte measurements.
authors.affiliation: The Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden. angelica.quartino@farmbio.uu.se
authors.forename: Angelica Linnea
authors.initials: AL
authors.lastname: Quartino
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects* / Q000276:immunology; D000077143:Docetaxel; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D018448:Models, Immunological; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D017711:Nonlinear Dynamics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel