PHARMACOKINETICS OF ALL-TRANS-RETINOIC ACID ADMINISTERED ON AN INTERMITTENT SCHEDULE

Purpose: Administration of all-trans-retinoic acid (ATRA) on a continu ous daily schedule results in a rapid and sustained decrease in plasma drug concentrations. This pharmacokinetic study was performed to dete rmine if administration of ATRA on an intermittent schedule could over come the rapid decrease in plasma drug concentration and provide repet itive periods of higher plasma drug exposure. Materials and Methods: A TRA was administered on repetitive cycles of 7 consecutive days of dru g followed by 7 days without drug. On the days of pharmacokinetic moni toring, following an overnight fast, a fixed single oral dose of 40 mg /m(2) was administered and frequent plasma samples were obtained over 8 hours, Patients had pharmacokinetic studies performed on the first a nd seventh days of the first week, and on the first day of the third a nd eleventh weeks. ATRA was measured in plasma with a reverse-phase hi gh-performance liquid chromatography (HPLC) assay. Results: Plasma exp osure to ATRA as measured by the area under the plasma concentration-t ime curve (AUG) decreased significantly during the first week of drug administration, from a mean of 145 +/- 26 mu mol/L . min on day 1 to 1 8 +/- 4 mu mol/L . min by day 7. Plasma ATRA concentrations at the sta rt 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 mu mol/L . min, respectively. Conclusion: An intermitt ent schedule of ATRA administration results in repetitive periods of e xposure 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.