Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel

Anticancer Drugs. 2001 Apr;12(4):315-23. doi: 10.1097/00001813-200104000-00003.


Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m(2), as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m(2), at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Anemia / chemically induced*
  • Area Under Curve
  • Breast Neoplasms / drug therapy
  • Carcinoma, Small Cell / drug therapy
  • Colonic Neoplasms / drug therapy
  • Dose-Response Relationship, Drug
  • Drug Carriers
  • Female
  • Gastrointestinal Diseases / chemically induced
  • Humans
  • Infusions, Intravenous
  • Lung Neoplasms / drug therapy
  • Male
  • Maximum Tolerated Dose
  • Methacrylates / chemistry
  • Middle Aged
  • Nervous System Diseases / chemically induced*
  • Ovarian Neoplasms / drug therapy
  • Paclitaxel / analogs & derivatives
  • Paclitaxel / chemical synthesis
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacokinetics*
  • Paclitaxel / toxicity*
  • Polymers / chemical synthesis
  • Polymers / chemistry
  • Polymers / pharmacokinetics*
  • Polymers / toxicity*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Prodrugs / toxicity
  • Remission Induction
  • Skin Neoplasms / secondary
  • Solubility
  • Taxoids / analogs & derivatives


  • Drug Carriers
  • Methacrylates
  • PNU 166945
  • Polymers
  • Prodrugs
  • Taxoids
  • Paclitaxel
  • hydroxypropyl methacrylate