Pharmacokinetic/pharmacodynamic interactions of intensive cyclophosphamide, cisplatin, and BCNU in patients with breast cancer

Combinations of alkylating agents in intensive doses with autologous hematopoietic cell support (AHCS) are commonly used to treat advanced, solid tumors. Relatively little is known about the pharmacokinetic or pharmacodynamic aspects of their use. The cyclophosphamide, cisplatin, and BCNU (CPA/cDDP/BCNU) regimen is often used in patients with breast cancer. In these individuals, the blood levels of BCNU vary by more than tenfold. In rats given BCNU, the blood level variability is associated with cisplatin pretreatment, and mean levels are much higher than those that occur when cisplatin pretreatment is omitted. These observations suggest that a major elimination pathway for BCNU is metabolic and is subject to cisplatin disruption. Between 30-50% of patients receiving the CPA/cDDP/BCNU regimen experience a steroid-responsive pulmonary injury that can be fatal if untreated. Blood levels of BCNU are positively correlated with the risk of pulmonary injury in these patients. Others have demonstrated that blood levels of CPA can be inversely correlated with the likelihood of cardiac toxicity and 2-year, relapse-free survival in patients with breast cancer. Emerging data suggest that circulating drug levels, rather than the calculated dose, best explain the variability of outcome in patients treated with combination alkylating agents and AHCS.