title: Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel.
abstract: 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.
authors.affiliation: The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. apjmt@slz.nl
authors.forename: J M
authors.initials: JM
authors.lastname: Meerum Terwogt
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: M
authors.initials: M
authors.lastname: Schot
authors.forename: I A
authors.initials: IA
authors.lastname: Mandjes
authors.forename: M G
authors.initials: MG
authors.lastname: Zurlo
authors.forename: M
authors.initials: M
authors.lastname: Rocchetti
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: F J
authors.initials: FJ
authors.lastname: Koopman
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008689:Methacrylates / Q000737:chemistry; D008875:Middle Aged; D009422:Nervous System Diseases / Q000139:chemically induced*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D012074:Remission Induction; D012878:Skin Neoplasms / Q000556:secondary; D012995:Solubility; D043823:Taxoids / Q000031:analogs & derivatives
chemical_list: D004337:Drug Carriers; D008689:Methacrylates; C111745:PNU 166945; D011108:Polymers; D011355:Prodrugs; D043823:Taxoids; D017239:Paclitaxel; C032802:hydroxypropyl methacrylate