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.

• Authors: A A Khan, J G Villablanca, C P Reynolds, V I Avramis
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 39 Issue 1-2 Pg. 34-41 ( 1996) ISSN: 0344-5704 [Print] Germany
• PMID: 8995497 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Keratolytic Agents
• Isotretinoin

Topics

• Administration, Oral
• Area Under Curve
• Bone Marrow Transplantation
• Child
• Child, Preschool
• Chromatography, High Pressure Liquid
• Combined Modality Therapy
• Drug Administration Schedule
• Female
• Humans
• Isotretinoin (administration & dosage, blood, pharmacokinetics)
• Keratolytic Agents (administration & dosage, blood, pharmacokinetics)
• Male
• Neuroblastoma (metabolism, therapy)
• Sex Factors
• Stereoisomerism