title: Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.
abstract: OBJECTIVE
  To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose.
  
  
  METHODS
  Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled. Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of a minimum of 3 patients starting at 110 mg/m2 and escalating by means of a modified Fibonacci scheme to 1,657 mg/m2/d. Pharmacologic samples were obtained on days 1 and 15. Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy.
  
  
  RESULTS
  Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m2/d. The MTD was 1,657 mg/m2/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient. Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (Cmax) 1 hour after ingestion. Linear increases in the area under the concentration-time curve (AUC) and Cmax were seen with linear increases in administered dose.
  
  
  CONCLUSIONS
  The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m2/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated.
authors.affiliation: Department of Medicine, North Shore University Hospital, New York University Medical College, Manhasset 11030, USA. budman@nshs.edu
authors.forename: D R
authors.initials: DR
authors.lastname: Budman
authors.forename: N J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: B
authors.initials: B
authors.lastname: Reigner
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: S M
authors.initials: SM
authors.lastname: Lichtman
authors.forename: E
authors.initials: E
authors.lastname: Berghorn
authors.forename: J
authors.initials: J
authors.lastname: Behr
authors.forename: R J
authors.initials: RJ
authors.lastname: Gordon
authors.forename: B
authors.initials: B
authors.lastname: Osterwalder
authors.forename: T
authors.initials: T
authors.lastname: Griffin
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil