Clinical results and pharmacokinetics of high-dose cytosine arabinoside (HD ARA-C).
Four patients with acute nonlymphoblastic leukemia and one malignant teratoma refractory to conventional chemotherapy were treated with high doses of cytosine arabinoside (HD ARA-C). They received up to 12 cycles of 1.8 to 3 g/m2 every 12 hours applied by 2-hour infusions. A total of 55 HD ARA-C infusions was performed. All leukemic patients responded. A complete clearance of blasts from the bone marrow was observed in two patients following 8-12 cycles of 3 g/m2. However, relapses occurred after three and seven weeks, in one case with resistance to HD ARA-C. The patient with malignant teratoma did not respond. No severe toxicity emerged even after repeated applications. Adverse reactions included moderate nausea and vomiting (4 patients), diarrhea (2 patients), hepatic dysfunction (1 patient), bone pain (1 patient), blurred vision (1 patient), conjunctivitis (1 patient), and exanthema with partial epidermiolysis (1 patient). Granulocytopenia occurring between 3-8 days after having started the therapy, subsided within 4-25 days. Plasma levels of ARA-C and the metabolite uracil arabinoside (ARA-U) were monitored. At steady state plasma concentrations of ARA-C were 32-97 microM (8-24 micrograms/ml). ARA-C disappeared from the plasma mono- or biphasic with a terminal half-life (t50%) of 7.8-12.6 minutes. The total clearance (Cl) of ARA-C varied between 1.7 and 2.9 liters/kg . h, and the distribution volume (Vss) between 0.44 and 0.86 liters/kg. Cerebrospinal fluid (CSF) levels of ARA-C reached 10-15% of steady state concentrations in plasma.
D000328:Adult; D001086:Arabinofuranosyluracil / Q000097:blood / Q000134:cerebrospinal fluid; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D013724:Teratoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D013997:Time Factors
D003561:Cytarabine; D001086:Arabinofuranosyluracil