title: Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases.
abstract: OBJECTIVE
  Cancer patients with predominantly hepatic metastases have poor outcomes and limited options. Hepatic arterial infusion (HAI) of a therapeutic agent may be an appropriate option for producing increased drug concentrations at the tumor sites while reducing systemic adverse effects in normal tissues.
  
  
  METHODS
  Patients with predominantly hepatic metastases (n = 48) were placed in 6 groups according to nanoparticle albumin-bound paclitaxel (nab-paclitaxel) dose level using a 3 + 3 design plus dose expansion for responsive tumor types. We evaluated the toxicity, antitumor activity, and pharmacokinetics of nab-paclitaxel delivered via HAI.
  
  
  RESULTS
  Thirty-eight and ten patients underwent HAI over 1 and 4 h, respectively, at doses of up to 300 mg/m(2). The treatment was safe and exhibited antitumor activity. Pharmacokinetic analyses revealed that HAI of nab-paclitaxel over 4 h resulted in markedly lower peak drug concentrations (C max) and longer times to peak concentration (T max) than that over 1 h. The self-control pharmacokinetic studies showed that HAI of nab-paclitaxel led to much lower C max and areas under the curve (AUC), compared with intravenous infusion.
  
  
  CONCLUSIONS
  HAI of nab-paclitaxel at up to 300 mg/m(2) over 4 h was well tolerated. Pharmacokinetic evaluation of C max, T max, and AUC implied that 4-h HAI enhanced hepatic extraction of nab-paclitaxel. Further preclinical and clinical studies are required to develop reliable methods of evaluation of hepatic extraction (clinicaltrials.gov registration number NCT00732836, first registered on August 8, 2008, and last updated on October 27, 2014).
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. siqingfu@mdanderson.org.
authors.forename: Fu
authors.initials: F
authors.lastname: Siqing
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Kirk S
authors.initials: KS
authors.lastname: Culotta
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Department of Pharmacy Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Myers
authors.affiliation: Department of Pharmacy Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhang
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.|Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Mo
authors.initials: MM
authors.lastname: Hou
authors.affiliation: UC San Diego Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial / Q000379:methods; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
keywords: Hepatic arterial infusion; Hepatic extraction; Liver metastasis; Nanoparticle albumin-bound paclitaxel; Pharmacokinetics; Regional therapy