Pharmacokinetics of all-trans retinoic acid in Japanese patients with acute promyelocytic leukemia

Abstract

All-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) is the first clinically used molecular-targeted therapy. ATRA therapy is the first-line therapy for APL because it weakly acts on leukemia cells, causes slight bone marrow suppression, which is inevitable with the use of anticancer drugs, and easily induces remission. However, development of resistance is a concern in ATRA therapy. Resistance may be caused by reduced ATRA concentration in the blood, expression of multi-drug resistance 1(MDR-1) gene, and mutation of PML/RAR fusion gene in APL cells. Therefore, various studies were performed to study the pharmacokinetics of ATRA. The pharmacokinetics of ATRA have been evaluated by measuring the concentration of ATRA and its metabolite (4-oxo retinoic acid) in the blood samples of APL patients from all over Japan. We determined (1) the pharmacokinetics of ATRA in pediatric patients, (2) effectiveness of intermittent administration of ATRA to maintain blood concentration in maintenance treatment, (3) increase in the concentration of 4-oxo retinoic acid in patients not responding to ATRA, (4) change in the pharmacokinetics of ATRA because of complications, and (5) effect of ATRA administration in pregnant women. This paper will provide an overview of previous reports and of the results of studies performed in Japan on the pharmacokinetics of ATRA.