The pharmacokinetics and pharmacodynamics of fludarabine phosphate in patients with renal impairment: A prospective dose adjustment study

A significant number of chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma and Waldenstrom's macroglobulinemia patients, treated with fludarabine phosphate (fludarabine), are elderly with diminished renal function. Since the kidney eliminates approximately 60% of fludarabine's primary metabolite (Fara-A), dose modification is necessary for all patients with impaired renal function including elderly patients. In this study, 22 patients with varying levels of renal function received a single intravenous dose of fludarabine (25 mg/m(3)), followed one week later by five (one per day) doses that were adjusted according to three predefined creatinine clearance (CLcr) levels. Relationships between renal function and F-ara-A clearance, F-ara-A exposure and F-ara-A -related toxicities were examined. The results demonstrate that total F-ara-A clearance correlated with CLcr and that F-ara-A exposure levels and patient toxicity profiles were similar across treatment groups. In conclusion, the CLcr-based fludarabine dose adjustments used in this study provided reasonably equivalent F-ara-A exposure with acceptable safety in patients with varying degrees of renal function.