Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel.
The population approach has been implemented prospectively in the clinical development of docetaxel (Taxotere). Overall 640 patients were evaluable for the population PK/PD analysis. The PK analysis evidenced significant covariates explaining the inter-patient variability of docetaxel clearance and the PK/PD analysis demonstrated that the variability in clearance was a significant predictor of several safety endpoints. In patients with clinical chemistry suggestive of mild to moderate liver function impairment (SGOT and/or SGPT > 1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN), total body clearance was lowered by an average of 27%. Specific safety analyses demonstrated that these patients are at a significantly higher risk than others for the development of severe docetaxel-induced side effects. Population PK/PD data were fully integrated into the regulatory dossier and in the labeling of docetaxel worldwide. Population PK/PD models are being used to elaborate a simulation model to predict the survival of patients with non-small cell lung cancer treated with docetaxel.
Bruno
R
R
Aventis Pharma Recherche et Developpement, Drug Metabolism and Pharmacokinetics, Antony, France.
Vivier
N
N
Veyrat-Follet
C
C
Montay
G
G
Rhodes
G R
GR
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D000077143:Docetaxel; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy; D017711:Nonlinear Dynamics; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011446:Prospective Studies; D012107:Research Design; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel