title: A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin.
abstract: BACKGROUND
  In preclinical models, the proton pump inhibitor pantoprazole enhances the antitumor activity of chemotherapeutic agents by improving drug distribution and by inhibiting autophagy.
  
  
  METHODS
  Patients with advanced solid tumors (n = 24) received doxorubicin 60 mg/m(2) and escalating doses of pantoprazole (80, 160, 240 and 360 mg) administered intravenously prior to doxorubicin. Blood samples were collected for pharmacokinetic studies. An optional biopsy was performed to evaluate doxorubicin concentration and pharmacodynamic markers of drug activity.
  
  
  RESULTS
  Twenty-four patients participated in the study (17 in the dose escalation phase and 7 in the dose expansion). Three patients experienced a dose limiting toxicity (grade 3 fatigue in the three cases), one patient at dose level 3 (pantoprazole 240 mg) and two patients at dose level 4 (pantoprazole 360 mg). Dose level 4 was considered to exceed the maximum tolerated dose. The recommended phase II dose was pantoprazole 240 mg and doxorubicin 60 mg/m(2). The most commonly observed toxicities included fatigue, neutropenia and leukopenia. Two patients achieved a confirmed partial response. Median maximum serum concentration of pantoprazole was 84.3 μM at 1-2 h after injection of pantoprazole 240 mg. No drug-drug interaction was observed. A single on-treatment tumor biopsy showed a sharply decreasing gradient in doxorubicin concentration and associated activity markers with increasing distance from tumor blood vessels.
  
  
  CONCLUSIONS
  Administration of high doses of pantoprazole in combination with doxorubicin is feasible. The recommended phase II dose of pantoprazole, 240 mg, will be evaluated in combination with docetaxel as first line in patients with castration-resistant prostate cancer.
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, 610 University Avenue, M5G 2 M9, Toronto, ON, Canada.
authors.forename: Irene
authors.initials: I
authors.lastname: Brana
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocana
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.forename: Albiruni R A
authors.initials: AR
authors.lastname: Razak
authors.forename: Christine
authors.initials: C
authors.lastname: Haines
authors.forename: Carol
authors.initials: C
authors.lastname: Lee
authors.forename: Sarah
authors.initials: S
authors.lastname: Douglas
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Bedard
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077402:Pantoprazole; D066066:Response Evaluation Criteria in Solid Tumors
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004317:Doxorubicin; D000077402:Pantoprazole