title: A phase I and pharmacokinetic study of a powder-filled capsule formulation of oral irinotecan (CPT-11) given daily for 5 days every 3 weeks in patients with advanced solid tumors.
abstract: OBJECTIVE
  Intravenous (i.v.) irinotecan is a cytotoxic topoisomerase I inhibitor with broad clinical activity in metastatic colorectal cancer and other tumors. The development of an oral formulation of irinotecan could enhance convenience and lessen the expense of palliative irinotecan delivery. This phase I study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of irinotecan given as a powder-filled capsule (PFC) daily for 5 days every 3 weeks.
  
  
  METHODS
  Patients with advanced solid tumors received escalating doses of oral irinotecan daily for 5 days every 3 weeks. Plasma samples were collected following the first and fifth doses of irinotecan during Cycle 1 to determine the PK of irinotecan and its major circulating metabolites: SN-38, SN-38G, and APC.
  
  
  RESULTS
  20 patients (median age 61.5 years, range 40-75; M/F 12/8; ECOG PS 0=5, 1=11, 2=4) received oral irinotecan at dose levels of 30 (n=3), 40 (n=3), 50 (n=6), and 60 (n=8) mg/m(2)/day. Of the eight patients enrolled at 60 mg/m(2), three patients experienced DLT (> or = grade 3) consisting of nausea (three patients), vomiting (three patients), diarrhea (two patients), and febrile neutropenia (two patients) for which all the three patients required hospitalization. Treatment of six patients at the 50-mg/m(2) dose level resulted in no DLT. Other toxicities observed include abdominal pain, alopecia, anorexia, and asthenia. After oral administration, irinotecan was rapidly absorbed into systemic circulation and converted to the active metabolite SN-38. Increasing dose levels resulted in a dose-dependent increase in mean exposure parameters (Cmax and AUC) of irinotecan and metabolites. Systemic exposure parameters (Cmax and AUC(0-24)) of irinotecan and SN-38 were comparable between days 1 and 5. The extent of conversion from irinotecan to SN-38 was approximately threefold higher after the oral administration compared to that previously observed after i.v. administration. The exposure parameters of irinotecan or SN-38 are of limited value in predicting severity of Cycle 1 toxicities in the twofold dose range evaluated.
  
  
  CONCLUSIONS
  Daily oral administration of irinotecan as the PFC formulation for 5 days every 3 weeks can safely deliver protracted exposure to SN-38, with the MTD of 50 mg/m(2)/d.
authors.affiliation: Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. pitot.henry@mayo.edu
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Sloan
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Atherton
authors.forename: Joseph
authors.initials: J
authors.lastname: Rubin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Duncan
authors.forename: Louis
authors.initials: L
authors.lastname: Denis
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: Donghua
authors.initials: D
authors.lastname: Yin
authors.forename: Amarnath
authors.initials: A
authors.lastname: Sharma
authors.forename: Patrick
authors.initials: P
authors.lastname: McGovren
authors.forename: Langdon L
authors.initials: LL
authors.lastname: Miller
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011208:Powders; D012680:Sensitivity and Specificity
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011208:Powders; D000077146:Irinotecan; D002166:Camptothecin