PHARMACOKINETIC STUDIES OF 13-CIS-RETINOIC ADD IN PEDIATRIC-PATIENTS WITH NEUROBLASTOMA FOLLOWING BONE-MARROW TRANSPLANTATION

A phase I clinical trial of 13-cis-retinoic acid (cis-RA) was undertak en to determine the maximally tolerated dose (MTD) and pharmacokinetic s (PK) of cis-RA following bone marrow transplantation (BMT) in childr en with high-risk neuroblastoma. Mean peak serum levels of cis-RA in 3 1 pediatric patients ranged from 4.9 to 8.9 mu M following doses of 10 0-200 mg/m(2) per day, divided into two doses every 12 h administered orally. The PK of cis-RA obeyed a single-compartment model following f irst-order absorption in the majority of patients. A linear increase i n the mean peak serum levels and area under the time-concentration cur ve (AUC) with increasing dose was observed, The average half-lives of absorption and elimination were 1.0 and 5.8 h, respectively. At the MT D of 160 mg/m(2) per day, the mean cis-RA peak serum concentration was 7.2 +/- 5.3 mu M. AUC values were not altered significantly during a 2-week course of treatment or over a long period of multiple courses. Levels of trans-retinoic acid, a metabolite of cis-RA, remained low bu t were similar on days 1 and 14, whereas the 4-oxo-13-cis-RA metabolit e had increased in 64% of patients by day 14. Peak serum cis-RA concen trations correlated with clinical toxicity as grade 3 to 4 toxicity wa s seen in 44% of patient-courses (8/18) with peak serum levels greater than or equal to 10 mu M, but only 13% (12/96) with peak serum levels < 10 mu M. These results show that cis-RA given at 160 mg/m(2) to chi ldren achieved serum concentrations known to be effective against neur oblastoma in vitro, and the PK for cis-RA differs from that reported f or trans-retinoic acid in children.