Cyclophosphamide, cisplatin, and carmustine: pharmacokinetics of carmustine following multiple alkylating-agent interactions

Abstract

Cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) constitute a combination alkylating-agent regimen commonly used with autologous marrow support. Its therapeutic effectiveness is accompanied by sporadic life-threatening and fatal toxicities, the most common of which is acute lung injury. We have previously shown that variation in the BCNU AUC can be correlated to the risk of pulmonary injury in patients receiving CPA/cDDP/BCNU. In an attempt to understand further the role of interpatient variation in drug pharmacokinetics (PK) with respect to pharmacodynamic outcomes, we evaluated the effect of pretreatment with CPA, cDDP, or both on BCNU PK in male Sprague-Dawley rats. The drug-administration pattern was designed to mimic that of the CPA/cDDP/BCNU regimen in patients. Each pretreatment increased both the absolute value of and the variation in BCNU AUC relative to the control values. These findings are consistent with an important rate-limiting elimination pathway for BCNU in rats and may explain the wide interpatient variability of BCNU AUC and the sporadic pulmonary toxicity seen in patients receiving CPA/cDDP/BCNU.