Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion.
Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m(2) with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 +/- 0.9 h. mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5-30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid retention (grade 2-3) after two to five courses.
Rosing
H
H
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. aphro@slz.nl
Lustig
V
V
van Warmerdam
L J
LJ
Huizing
M T
MT
ten Bokkel Huinink
W W
WW
Schellens
J H
JH
Rodenhuis
S
S
Bult
A
A
Beijnen
J H
JH
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000469:Alkaline Phosphatase / Q000097:blood / Q000187:drug effects; D000505:Alopecia / Q000139:chemically induced; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D000077143:Docetaxel; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D013280:Stomatitis / Q000139:chemically induced; D043823:Taxoids; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D017239:Paclitaxel