Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions.
OBJECTIVE
The paclitaxel vehicle Cremophor EL (CrEL) profoundly influences the cellular distribution of paclitaxel in human blood in vitro by a concentration-dependent decrease of the unbound drug fraction. Because CrEL clearance increases by extending the infusion duration from 3 to 24 hours, we hypothesized that exposure to unbound paclitaxel might also be schedule-dependent.


METHODS
CrEL and unbound paclitaxel pharmacokinetics were prospectively analyzed in 29 patients with advanced solid tumors treated with paclitaxel 100 mg/m(2) given as a 1-hour (n = 15) or 3-hour (n = 14) intravenous infusion.


RESULTS
The systemic exposure (area under the curve [AUC]) to CrEL was significantly higher with the 1-hour as compared with the 3-hour schedule (80.2 +/- 24.2 v. 48.5 +/- 24.1 microL x h/mL; P =.002). In contrast, the AUC of unbound paclitaxel was substantially reduced after the 1-hour infusion (0.50 +/- 0.10 v. 0.62 +/- 0.12 micromol/L x h; P =.009). Similarly, clearance and volume of distribution were significantly dependent on infusion duration (P <.005). A trend was observed toward more severe hematologic toxicity with the 3-hour schedule (P =.053), consistent with increased exposure to unbound drug.


CONCLUSIONS
Overall, these findings explain, at least in part, previous observations that short-infusion schedules of paclitaxel lack significant myelotoxicity, whereas potentially CrEL-related side effects, including peripheral neuropathy, are augmented.
Gelderblom
Hans
H
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands.
Mross
Klaus
K
ten Tije
Albert J
AJ
Behringer
Dirk
D
Mielke
Stephan
S
van Zomeren
Desirée M
DM
Verweij
Jaap
J
Sparreboom
Alex
A
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004334:Drug Administration Schedule; D005260:Female; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013501:Surface-Active Agents / Q000008:administration & dosage; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D013501:Surface-Active Agents; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol