title: Phase I and pharmacokinetic study of AI-850, a novel microparticle hydrophobic drug delivery system for paclitaxel.
abstract: OBJECTIVE
  AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacokinetics of paclitaxel in this new formulation, and seek evidence of anticancer activity.
  
  
  METHODS
  This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concentrations were measured by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m(2). Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m(2) AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas.
  
  
  CONCLUSIONS
  The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m(2). The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center and University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.forename: Richard C
authors.initials: RC
authors.lastname: Walovitch
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Perez
authors.forename: Kathleen
authors.initials: K
authors.lastname: MacKay
authors.forename: David P
authors.initials: DP
authors.lastname: Tuck
authors.forename: Cecilia
authors.initials: C
authors.lastname: Simmons
authors.forename: Susan
authors.initials: S
authors.lastname: Hammond
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mita
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Stone
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D002214:Capsules / Q000737:chemistry*; D002853:Chromatography, Liquid / Q000379:methods; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C522040:AI-850; D000972:Antineoplastic Agents, Phytogenic; D002214:Capsules; D017239:Paclitaxel