title: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.
abstract: OBJECTIVE
  The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome.
  
  
  METHODS
  PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models.
  
  
  RESULTS
  PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication.
  
  
  CONCLUSIONS
  First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.
authors.affiliation: Drug Metabolism and Pharmacokinetics Department, Rhône-Poulenc Rorer, Antony, France. rene.bruno@rp_rorer.fr
authors.forename: R
authors.initials: R
authors.lastname: Bruno
authors.forename: D
authors.initials: D
authors.lastname: Hille
authors.forename: A
authors.initials: A
authors.lastname: Riva
authors.forename: N
authors.initials: N
authors.lastname: Vivier
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinnink
authors.forename: A T
authors.initials: AT
authors.lastname: van Oosterom
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: F V
authors.initials: FV
authors.lastname: Fossella
authors.forename: V
authors.initials: V
authors.lastname: Valero
authors.forename: J R
authors.initials: JR
authors.lastname: Rigas
authors.forename: A D
authors.initials: AD
authors.lastname: Seidman
authors.forename: B
authors.initials: B
authors.lastname: Chevallier
authors.forename: P
authors.initials: P
authors.lastname: Fumoleau
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: P M
authors.initials: PM
authors.lastname: Ravdin
authors.forename: L B
authors.initials: LB
authors.lastname: Sheiner
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy; D000077143:Docetaxel; D004487:Edema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011446:Prospective Studies; D043823:Taxoids
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel