Pharmacokinetic studies of 13- cis -retinoic acid in pediatric patients with neuroblastoma following bone marrow transplantation

Abstract

A phase I clinical trial of 13-cis-retinoic acid (cis-RA) was undertaken to determine the maximally tolerated dose (MTD) and pharmacokinetics (PK) of cis-RA following bone marrow transplantation (BMT) in children with high-risk neuroblastoma. Mean peak serum levels of cis-RA in 31 pediatric patients ranged from 4.9 to 8.9 microM following doses of 100-200 mg/m2 per day, divided into two doses every 12 h administered orally. The PK of cis-RA obeyed a single-compartment model following first-order absorption in the majority of patients. A linear increase in the mean peak serum levels and area under the time-concentration curve (AUC) with increasing dose was observed. The average half-lives of absorption and elimination were 1.0 and 5.8 h, respectively. At the MTD of 160 mg/m2 per day, the mean cis-RA peak serum concentration was 7.2 +/- 5.3 microM. 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 but were similar on days 1 and 14, whereas the 4-oxo-13-cis-RA metabolite had increased in 64% of patients by day 14. Peak serum cis-RA concentrations correlated with clinical toxicity as grade 3 to 4 toxicity was seen in 44% of patient-courses (8/18) with peak serum levels > 10 microM, but only 13% (12/96) with peak serum levels < 10 microM. These results show that cis-RA given at 160 mg/m2 to children achieved serum concentrations known to be effective against neuroblastoma in vitro, and the PK for cis-RA differs from that reported for trans-retinoic acid in children.

Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma – a study of the United Kingdom Children's Cancer Study Group

“…It is notable that the plasma concentrations achieved in the current study are up to four-fold lower than those reported in a phase I study of the same formulation (Khan et al, 1996). The reasons for this difference are not easily identified.…”

“…Analysis of patient samples from a phase I study of 13-cisRA previously suggested increasing levels of the metabolite 4-oxo-13-cisRA during a course of treatment, although actual concentrations were not quantified (Khan et al, 1996).…”

Interferon-? cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells

“…61 Based on observations that RA can also induce differentiation of neuroblastoma cell lines in vitro, 16 -18 RA has been used for several clinical trials in neuroblastoma patients with variable results. [37][38][39][40] However, a recent study using high-dose 13-cis RA treatment after myeloablative therapy and autologous bone marrow transplantation showed encouraging results. 41 Since differentiation and/or growth arrest induced by RA, TPA or vitamin D 3 was shown to be potentiated by IFN-␥ in several cell types, [42][43][44][45][46][47] the aim of our investigation was to determine whether IFN-␥ would synergize with RA or TPA to induce differentiation and growth inhibition in neuroblastoma cells.…”

“…Our results together with those of Wuarin et al 50 and a publication by Cornaglia et al, 48 reporting that combined therapy with RA and IFN-␥ inhibited tumor formation of LA-N-5 cells injected in nude mice, suggest that RA and IFN-␥ in combination may be of therapeutical interest. Presently both RA [37][38][39][40] and IFN-␥ 62 have been used as single agents in clinical trials for cancer therapy. This is a good basis for combination therapy with the 2 agents.…”

“…Long-term remissions were observed occasionally in neuroblastoma patients in clinical trials using all-trans-RA or 13-cis RA. [37][38][39][40] However, high-dose 13-cis RA treatment after autologous bone marrow transplantation showed encouraging results in a recent study. 41 Studies of cell types other than neuroblastoma have demonstrated that IFN-␥ potentiates differentiation and/or growth arrest induced by RA or vitamin D 3 in acute promyelocytic leukemia and myelomonocytic tumor cells [42][43][44][45] and in mammary and cervical carcinoma cells.…”