POPULATION PHARMACOKINETICS PHARMACODYNAMICS OF DOCETAXEL IN PHASE-IISTUDIES IN PATIENTS WITH CANCER/

Purpose: The population pkarmacokinetic/pharmacodynamic (PK/PD) approa ch was prospectively integrated in the clinical development of docetax el to assess the PK profile in a large population of patients and inve stigate systemic exposure as a prognostic factor for clinical outcome, Patients and Methods: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limit ed-sampling schedules, Bayesian estimates of clearance (CL), area unde r 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 lu ng cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention, PK/P D analysis was conducted using logistic and Cox multivariate regressio n models, Results: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were as sessable for PK (640 patients), First-course docetaxel AUC was a signi ficant predictor (P = .0232) of TTP in NSCLC (n = 151), Docetaxel CL w as ct strong independent predictor (P < .0001) of both grade 4 neutrop enia and febrile neutropenia (n = 582). Cumulative dose was the strong est predictor (P < .0001) of the time to onset of fluid retention (n = 631). However,the duration of exposure over 0.20 mu mol/L (0.16 mu g/ mL) at first course was an independent predictor (P = .0029). Few pati ents (n = 25, 4%) received the recommended dexamethasone premedication . Conclusion: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulativ e in nature. Patients with elevated hepatic enzymes have a 27% reducti on in docetaxel CL and are at a higher risk of toxicity, A starting do se of 75 mg/m(2) is currently being evaluated in this population. pros pective implementation of large-scale population PK/PD evaluation is f easible in early drug development and this approach generates clinical ly relevant findings, (C) 1998 by American Society of Clinical Oncolog y.