Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion

Most studies using high-dose cytarabine (ara-c) for the therapy of acute leukemia have employed intermittent short infusions. In this study, we have evaluated the pharmacology and toxicity of high-dose ara-c by 72-hour continuous infusion. Plasma ara-c concentrations varied from 3.6 microM at the starting dose of 4 g/m2/72 hours to 22.6 microM at 18 g. Plasma clearance appeared to decrease progressively at doses greater than 10 g, suggesting that the route of elimination was saturable. CSF ara-c concentrations ranged from 1.2 microM at 4 g to 4.1 microM at 18 g; the ratio of CSF to plasma ara-c decreased progressively from 0.33 at 4 g to 0.18 at 18 g. The toxic effects were significant and included myelosuppression, nausea, and vomiting in all patients. No single dose-limiting toxicity was identified. Further dose escalation was precluded by combined organ system effects, which included hepatic, pulmonary, renal, and gastrointestinal toxic effects. Attempts to incorporate a 72-hour infusion of ara-c into a combination chemotherapy regimen should proceed cautiously with a starting dose of 6 g/m2/72 hours.