David F Kisor1. 1. Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810-6000, USA. d-kisor@onu.edu
Abstract
OBJECTIVE: To present the pharmacology and pharmacokinetics of nelarabine, 9-beta-D-arabinofuranosylguanine (ara-G) and intraleukemic cellular pharmacokinetics of 9-beta-D-arabinofuranosylguanine triphosphate (ara-GTP) generated from the administration of nelarabine, and clinical and safety information relative to nelarabine use in the treatment of hematologic malignancies. DATA SOURCES: MEDLINE (1966-December 2004) was searched using the English-language key terms 2-amino-6-methoxypurine arabinoside, 506U78, and nelarabine. Data were also obtained from published abstracts. STUDY SELECTION AND DATA EXTRACTION: Clinical studies evaluating the pharmacokinetics of nelarabine, ara-G, and cellular ara-GTP and use of nelarabine, alone or in combination with other agents for the treatment of hematologic malignancies, were included in this review. DATA SYNTHESIS: Nelarabine is the water-soluble, 6-methoxy analog of 9-beta-D-ara-G. Nelarabine is readily converted to ara-G by endogenous adenosine deaminase. The half-life of nelarabine is approximately 15 minutes compared with 2-4 hours for ara-G. The clearance of ara-G is higher in children than in adults (0.312 vs 0.213 L x h(-1) x kg(-1)). Intracellular ara-GTP elimination is slow relative to nelarabine and ara-G. In pediatric and adult patients, neurologic toxicity is dose limiting. Severe myelosuppression was not consistently observed. Major responses were seen in patients with T-cell malignancies. Patients who responded had significantly higher intracellular ara-GTP concentrations compared with those who did not respond. CONCLUSIONS: Nelarabine is an effective ara-G prodrug. Nelarabine has significant activity against malignant T-cells and appears to be an important addition to treatments of various leukemias.
OBJECTIVE: To present the pharmacology and pharmacokinetics of nelarabine, 9-beta-D-arabinofuranosylguanine (ara-G) and intraleukemic cellular pharmacokinetics of 9-beta-D-arabinofuranosylguanine triphosphate (ara-GTP) generated from the administration of nelarabine, and clinical and safety information relative to nelarabine use in the treatment of hematologic malignancies. DATA SOURCES: MEDLINE (1966-December 2004) was searched using the English-language key terms 2-amino-6-methoxypurine arabinoside, 506U78, and nelarabine. Data were also obtained from published abstracts. STUDY SELECTION AND DATA EXTRACTION: Clinical studies evaluating the pharmacokinetics of nelarabine, ara-G, and cellular ara-GTP and use of nelarabine, alone or in combination with other agents for the treatment of hematologic malignancies, were included in this review. DATA SYNTHESIS: Nelarabine is the water-soluble, 6-methoxy analog of 9-beta-D-ara-G. Nelarabine is readily converted to ara-G by endogenous adenosine deaminase. The half-life of nelarabine is approximately 15 minutes compared with 2-4 hours for ara-G. The clearance of ara-G is higher in children than in adults (0.312 vs 0.213 L x h(-1) x kg(-1)). Intracellular ara-GTP elimination is slow relative to nelarabine and ara-G. In pediatric and adult patients, neurologic toxicity is dose limiting. Severe myelosuppression was not consistently observed. Major responses were seen in patients with T-cell malignancies. Patients who responded had significantly higher intracellular ara-GTP concentrations compared with those who did not respond. CONCLUSIONS:Nelarabine is an effective ara-G prodrug. Nelarabine has significant activity against malignant T-cells and appears to be an important addition to treatments of various leukemias.
Authors: Christian Späth; Mandy Schönau; Sophie Gaubert; Thomas Neumann; Christian A Schmidt; Florian H Heidel; William H Krüger Journal: Ann Hematol Date: 2022-06-17 Impact factor: 4.030