The Shape of the Myelosuppression Time-course is Related to the Probability of Developing Neutropenic Fever in Patients with Docetaxel-induced Grade IV Neutropenia
Emma K. Hansson, Lena E. Friberg
Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala Sweden
Objectives: Chemotherapy-induced neutropenic episodes are associated with the risk of developing the life-threatening condition febrile neutropenia (FN), defined as fever ≥ 38.3 °C in combination with grade IV neutropenia, i.e. neutrophil count < 0.5 x 109/L. The aim of the present study was to describe the time-course of myelosuppression in patients treated with docetaxel and to investigate if the probability of developing FN in patients with grade IV neutropenia is random or dependent on the shape of the predicted myelosuppression time-course and on other proposed risk factors .
Methods: Neutrophil counts (n=517) from 140 of totally 244 breast cancer patients (FN =26 episodes) with observed grade IV neutropenia during the first course of docetaxel treatment (100 mg/m2) were included in the analysis . Concentration-time profiles of docetaxel were predicted using typical population PK parameters . A semi-physiological myelosuppression model  was fitted to the neutrophil observations using the LAPLACE method in NONMEM VI. The neutrophil data were Box-Cox transformed with a factor 0.2 to obtain symmetrically distributed residuals around zero. The half life of neutrophils was fixed to 7 hours. The myelosuppression model parameters (baseline neutrophil count, mean transit time (MTT) and drug effect parameter EC50), myelosuppression descriptors (nadir and duration of grade IV neutropenia) and proposed risk factors  (age, performance status, haemoglobin (Hb) and liver function) were explored to be related to the FN data by logistic regression.
Results: The myelosuppression model could well characterize the neutrophil-time course following docetaxel treatment and resulted in similar system-related parameter estimates as previously observed . A sigmoidal Emax model described the data better than a linear drug effect relationship. The myelosuppression model parameters EC50 and MTT were both significantly related to the probability of developing FN where low values indicate increased risk. None of the evaluated risk factors or myelosuppression descriptors was found significant.
Conclusions: The probability to develop FN is dependent on the myelosuppression time-course. Patients with high drug sensitivity and a fast neutrophil decline have a higher probability to develop FN compared with other patients who experience grade IV neutropenia.
 Aapro MS., et al., European J Cancer; 42:2433-2453, 2006.
 O'shaughenssy J et al., J Clin Oncol; 20:2812-2822, 2002.
 Bruno R., et al., J Pharmacokinet Biopharm; 24:153-72, 1996.
 Friberg LE., et al., J Clin Oncol; 20:4713-21, 2002.