Pharmacokinetics of all-trans retinoic acid (ATRA) in patients with renal cancer concomitantly treated with interferon alpha 2A (IFN)

Eight patients with advanced renal cell cancer were treated in a phase II trial with interferon alpha 2a (9-18 MIU/m(2) subcutaneously) three days a week and all-trans retinoic acid (ATRA) 100 mg/m(2)/day orally in three equal fractions 7 h apart. All eight patients underwent pharmacokinetic studies on day 1 of therapy, and six were again studied on day 90. A new simple and rapid HPLC method was developed to measure plasma concentrations of ATRA, with a detection limit of 5 ng/ml at 340 nn. Blood samples were drawn for 7 h following 1/3 oral doses of 100 mg ATRA/m(2). On day 1, peak plasma levels of ATRA (56 +/- 37 ng/ml, mean +/- SD) were reached after 1-5.5 h. Classically, a significant decrease in both peak plasma levels and the area under the concentration-time curve was observed after 2-6 weeks of ATRA treatment. In our preliminary study, concomitant IFN treatment increased peak plasma levels of ATRA after at least 3 months of treatment in 4 patients and reduced the clearance rate in 4 patients. On day 90, a patient who had not taken INF the previous day and in whom ATRA was undetectable developed a clinical relapse.