Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion.
The present study was conducted to compare the pharmacokinetics and pharmacodynamics (PD) of paclitaxel between Phase I trials of 3- and 24-h infusions and to determine the most informative pharmacokinetic parameter to describe the PD. Twenty-seven patients were treated in a Phase I study of paclitaxel by a 3-h infusion at one of six doses: 105, 135, 180, 210, 240, and 270 mg/m2. Pharmacokinetic data were obtained from all patients. Paclitaxel concentrations were measured in the plasma and urine using HPLC. The pharmacokinetics and PD were compared with those of a Phase I trial of paclitaxel by a 24-h schedule previously performed. The maximum tolerated dose of paclitaxel by a 3-h infusion was determined to be 240 mg/m2. The major toxicities were granulocytopenia, neuromuscular toxicities, and hypotension. Apparent differences in pharmacodynamic relationships for the change in granulocytes with dose, peak concentration, and areas under the concentration versus time curve were observed between the 3- and 24-h schedules. However, the relationship between the duration of plasma concentration above 0.05 microM and the change in granulocytes could be fitted to the same sigmoid maximum effect model in either schedule (P < 0.01). There were no clear relationships between peripheral neuropathy or hypotension and any pharmacokinetic parameters. The pharmacokinetics and PD of paclitaxel were schedule dependent. The duration of plasma concentration above 0.05 microM could be a common pharmacokinetic parameter predicting granulocytopenia for both schedules.
Ohtsu
T
T
Divisions of Oncology/Hematology and Respiratory Disease, Department of Medicine, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-city, Chiba 277.
Sasaki
Y
Y
Tamura
T
T
Miyata
Y
Y
Nakanomyo
H
H
Nishiwaki
Y
Y
Saijo
N
N
D000380:Agranulocytosis / Q000139:chemically induced; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D003907:Dexamethasone / Q000627:therapeutic use; D004155:Diphenhydramine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000517:prevention & control; D006634:Histamine H1 Antagonists / Q000627:therapeutic use; D006635:Histamine H2 Antagonists / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D007958:Leukocyte Count / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011899:Ranitidine / Q000627:therapeutic use; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D003907:Dexamethasone; D011899:Ranitidine; D004155:Diphenhydramine; D017239:Paclitaxel