title: Population pharmacokinetic-pharmacodynamic modeling and model-based prediction of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer.
abstract: OBJECTIVE
  Docetaxel is used to treat many cancers, and neutropenia is the dose-limiting factor for its clinical use. A population pharmacokinetic-pharmacodynamic (PK-PD) model was introduced to predict the development of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Forty-seven advanced or recurrent Japanese patients with NSCLC were enrolled. Patients received 50 or 60 mg/m2docetaxel as monotherapy, and blood samples for a PK analysis were collected up to 24 h after its infusion. Laboratory tests including absolute neutrophil count data and demographic information were used in population PK-PD modeling. The model was built by NONMEM 7.2 with a first-order conditional estimation using an interaction method. Based on the final model, a Monte Carlo simulation was performed to assess the impact of covariates on and the predictability of neutropenia.
  
  
  RESULTS
  A three-compartment model was employed to describe PK data, and the PK model adequately described the docetaxel concentrations observed. Serum albumin (ALB) was detected as a covariate of clearance (CL): CL (L/h) = 32.5 × (ALB/3.6)0.965× (WGHT/70)3/4. In population PK-PD modeling, a modified semi-mechanistic myelosuppression model was applied, and characterization of the time course of neutrophil counts was adequate. The covariate selection indicated that α1-acid glycoprotein (AAG) was a predictor of neutropenia. The model-based simulation also showed that ALB and AAG negatively correlated with the development of neutropenia and that the time course of neutrophil counts was predictable.
  
  
  CONCLUSIONS
  The developed model may facilitate the prediction and care of docetaxel-induced neutropenia.
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fukae
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirota
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Yamahashi
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ieiri-ttr@umin.ac.jp.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008175:Lung Neoplasms / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009010:Monte Carlo Method; D009503:Neutropenia / Q000139:chemically induced* / Q000453:epidemiology; D009961:Orosomucoid / Q000032:analysis; D011153:Population; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012709:Serum Albumin / Q000032:analysis; D043823:Taxoids / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009961:Orosomucoid; D012709:Serum Albumin; D043823:Taxoids; D000077143:Docetaxel
keywords: Docetaxel; Modeling and simulation; NONMEM; Neutropenia; Pharmacometrics; pharmacokinetic–pharmacodynamic analysis