Nonpredictable pharmacokinetic behavior of high-dose cyclophosphamide in combination with cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea

Our objective was to assess whether the total area under the curve (AUC) of high-dose cyclophosphamide (CPA), combined with cisplatin and 1,3-bis(2- chloroethyl)-1-nitrosourea, could be predicted from its AUC on the first day of treatment. We reviewed the AUC of CPA in 470 patients who underwent pharmacokinetic monitoring of the drug. All patients received the same high- dose regimen of CPA, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (STAMP-I) with identical antiemetic support. Subsequently, patients who experienced a toxic death, relapsed after high-dose chemotherapy, or remained relapse-free at a minimum follow-up of 1 year after high-dose chemotherapy were analyzed for a correlation between the total AUC of CPA and both relapse-free survival and toxic death. The AUC of CPA decreased from day 1 to day 2 in most patients. However, its changes from day 2 to day 3 varied significantly. Neither the value of AUC on day 1 nor its decreasing trend from day 2 to day 3 could predict the AUC on day 3 and the total AUC. Our pharmacodynamic analysis in 335 patients failed to show a correlation between the total AUC of CPA and either toxic death or relapse-free survival. The significant intersubject variability in the AUC of CPA makes the final AUC of the drug unpredictable from an initial measurement on day 1. Thus, in this combination, measurement of levels of parent CPA, with the objective of real- time therapeutic monitoring of this drug, is not informative.