title: Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers.
abstract: BACKGROUND
  Capecitabine and irinotecan have demonstrated in vitro synergistic anti-cancer activity, and both are substrates for carboxyl esterases (CES). We conducted a study to identify a safe dose and potential drug-drug interactions of this combination.
  
  
  METHODS
  This was an open-label phase I dose escalation trial. Irinotecan was given as a 30 min infusion on days 1 and 8, and capecitabine on days 1-14 of a 21-day cycle. Plasma for pharmacokinetic analyses was drawn on days 1 and 8.
  
  
  RESULTS
  Forty-seven patients with advanced solid tumors received 202 cycles of chemotherapy in 6 dose cohorts. At the highest dose tested, 1 of 3 patients developed fatal neutropenia and gram-negative sepsis. At dose level 5 (100/2000), 2 of 28 patients developed cycle 1 DLT-grade 3 diarrhea/vomiting, and grade 3 diarrhea. Responses were observed in 9 of 35 (5 of 9 ovarian cancer) evaluable patients. The AUC((0-last)) of irinotecan, SN-38G, and APC were similar on days 1 and 8. However, SN-38 T(max) was longer on Day 8 (0.88 h vs. 1.23 h, p = 0.012). While SN-38 AUC((0-last)) was lower on day 8 by 35%, this was not statistically significant (p = 0.123).
  
  
  CONCLUSIONS
  Capecitabine results in a significantly delayed conversion of irinotecan to SN-38, suggesting drug-drug interaction at the level of CES. This suggests caution should be used when irinotecan is combined with substrates of CES, and warrants further study. The combination of irinotecan and capecitabine is safe and well tolerated at 100/2000, and warrants further evaluation in ovarian and breast cancer.
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine and Cancer Center, Bronx, NY 10461, USA. sgoel@montefiore.org
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.forename: Kavita
authors.initials: K
authors.lastname: Desai
authors.forename: Sirisha
authors.initials: S
authors.lastname: Karri
authors.forename: Radharani
authors.initials: R
authors.lastname: Gollamudi
authors.forename: Imran
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Anca
authors.initials: A
authors.lastname: Bulgaru
authors.forename: Andreas
authors.initials: A
authors.lastname: Kaubisch
authors.forename: Gary
authors.initials: G
authors.lastname: Goldberg
authors.forename: Mark
authors.initials: M
authors.lastname: Einstein
authors.forename: Fernando
authors.initials: F
authors.lastname: Camacho
authors.forename: Sharyn
authors.initials: S
authors.lastname: Baker
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood; D000069287:Capecitabine; D043182:Carboxylesterase / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: C100720:RPR 121056; C106003:SN38-Glu; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D043182:Carboxylesterase; D005472:Fluorouracil; D002166:Camptothecin