title: The shape of the myelosuppression time profile is related to the probability of developing neutropenic fever in patients with docetaxel-induced grade IV neutropenia.
abstract: OBJECTIVE
  Chemotherapy-induced neutropenia is associated with the risk of developing febrile neutropenia (FN). The aim was to describe the time course of myelosuppression in breast cancer patients treated with docetaxel and to investigate how the shape of the predicted myelosuppression time course and earlier proposed risk factors influence the probability of developing FN.
  
  
  METHODS
  Neutrophil counts from 140 breast cancer patients with observed grade IV neutropenia during the first course of docetaxel treatment were included. Twenty-six of the patients (19%) experienced FN. The myelosuppression time course was described using a semi-mechanistic myelosuppression model in NONMEM. The individual myelosuppression model parameters [baseline neutrophil count, mean transit time (MTT) and drug effect parameter (EC(50))], myelosuppression descriptors (nadir, duration of grade IV neutropenia) and earlier suggested risk factors (age, performance status, haemoglobin and liver function) were explored to be related to FN by logistic regression.
  
  
  RESULTS
  The neutrophil time course following docetaxel treatment was well described by the model. EC(50) and MTT were both significantly related to the probability of developing FN where low parameter values result in a rapid decline, low nadir and an increased risk of FN. None of the evaluated risk factors or myelosuppression descriptors were significant.
  
  
  CONCLUSIONS
  The probability to develop FN in patients who experience grade IV neutropenia was dependent on the myelosuppression time profile. Patients with a rapid neutrophil decline and high drug sensitivity had a higher probability to develop FN. Model-based parameter estimates were superior predictors over descriptive values such as the nadir or duration of neutropenia.
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden. emma.hansson@farmbio.uu.se
authors: Emma K
authors: EK
authors: Hansson
authors: Lena E
authors: LE
authors: Friberg
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D017326:Clinical Trials, Phase III as Topic; D000077143:Docetaxel; D005260:Female; D005334:Fever / Q000097:blood / Q000139:chemically induced / Q000209:etiology*; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced*; D012307:Risk Factors; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel