Pharmacology of all-trans-retinoic acid in children with acute promyelocytic leukemia.
BACKGROUND
Due to severe side effects in virtually all children treated with a standard dose of 45 mg/m(2)/day all-trans-retinoic acid (ATRA) for acute promyelocytic leukemia (APL) the AML-BFM study group reduced the dosage to 25 mg/m(2)/day. For the lack of data on the use of ATRA at this dosage in children with APL, the study group further decided to evaluate the pharmacokinetics and metabolism of ATRA in children.


METHODS
Twenty-three pharmacokinetic and metabolic profiles of ATRA were studied in 14 children (aged 0.9-18.4 years) with APL. Eleven plasma samples were collected over a period of 8 hr and analyzed for ATRA and its metabolites by high-performance liquid chromatography.


RESULTS
Peak plasma concentrations of ATRA were characterized by wide interpatient variability (range: 28.6-513.0 nM). Compared to adults the same metabolic pathways were observed in children. Even though peak plasma concentrations were in the lower range of those considered effective in vitro, ATRA side effects, notably neurotoxicity, still required dose reduction, treatment break, or drug withdrawal in eight patients. In this small number of patients, neurotoxicity could not be related to age or any specific level of ATRA or metabolites in the plasma. Plasma concentrations of vitamin A, however, were significantly higher in those patients, who developed signs of neurotoxicity (P = 0.03, Mann-Whitney Rank Sum test).


CONCLUSIONS
Considering the low plasma concentrations and the persistence of toxicity in spite of dose reduction intermittent dosing schedules might be considered as an alternative to further dose reduction of ATRA in the treatment of APL especially in children, who might be at risk of ATRA-induced neurotoxicity.
Lanvers
Claudia
C
University Children's Hospital Muenster, Department of Pediatric Hematology and Oncology, Albert-Schweitzer-Str. 33, Germany.
Reinhardt
Dirk
D
Dübbers
Angelika
A
Wagner-Bohn
Alexandra
A
Creutzig
Ursula
U
Ritter
Joerg
J
Boos
Joachim
J
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008297:Male; D020258:Neurotoxicity Syndromes / Q000209:etiology; D012176:Retinoids / Q000097:blood; D018709:Statistics, Nonparametric; D014212:Tretinoin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D012176:Retinoids; D014212:Tretinoin