title: Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule.
abstract: OBJECTIVE
  Administration of all-trans-retinoic acid (ATRA) on a continuous daily schedule results in a rapid and sustained decrease in plasma drug concentrations. This pharmacokinetic study was performed to determine if administration of ATRA on an intermittent schedule could overcome the rapid decrease in plasma drug concentration and provide repetitive periods of higher plasma drug exposure.
  
  
  METHODS
  ATRA was administered on repetitive cycles of 7 consecutive days of drug followed by 7 days without drug. On the days of pharmacokinetic monitoring, following an overnight fast, a fixed single oral dose of 40 mg/m2 was administered and frequent plasma samples were obtained over 8 hours. Patients had pharmacokinetic studies performed on the first and seventh days of the first week, and on the first day of the third and eleventh weeks. ATRA was measured in plasma with a reverse-phase high-performance liquid chromatography (HPLC) assay.
  
  
  RESULTS
  Plasma exposure to ATRA as measured by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from a mean of 145 +/- 26 mumol/L.min on day 1 to 18 +/- 4 mumol/L.min by day 7. Plasma ATRA concentrations at the start of weeks 3 and 11 of this every-other-week schedule were equivalent to those achieved on day 1 of treatment, with mean AUCs of 177 +/- 39 and 128 +/- 30 mumol/L.min, respectively.
  
  
  CONCLUSIONS
  An intermittent schedule of ATRA administration results in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment. Phase II trials to evaluate the role of intermittent schedules of administration for ATRA are planned.
authors.affiliation: Pediatric Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
authors.forename: J
authors.initials: J
authors.lastname: Bailey
authors.forename: J
authors.initials: J
authors.lastname: Pluda
authors.forename: D G
authors.initials: DG
authors.lastname: Poplack
authors.forename: S
authors.initials: S
authors.lastname: Bauza
authors.forename: R F
authors.initials: RF
authors.lastname: Murphy
authors.forename: R
authors.initials: R
authors.lastname: Yarchoan
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D006207:Half-Life; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008875:Middle Aged; D012074:Remission Induction; D012514:Sarcoma, Kaposi / Q000150:complications; D014212:Tretinoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015854:Up-Regulation
chemical_list: D014212:Tretinoin