Cyclophosphamide has been in clinical use for the treatment of malignant disease for over 30 years. It remains one of the most useful
anticancer agents, and is also widely used for its immunosuppressive properties.
Cyclophosphamide is inactive until it undergoes hepatic transformation to form
4-hydroxycyclophosphamide, which then breaks down to form the ultimate
alkylating agent,
phosphoramide mustard. Sensitive and specific methods are now available for the measurement of
cyclophosphamide, its metabolites and its stereoisomers in plasma and urine. The pharmacokinetics of
cyclophosphamide have been understood for many years; those of the cytotoxic metabolites have been described more recently. The pharmacokinetics are not significantly altered in the presence of hepatic or
renal insufficiency. As activity resides exclusively in the metabolites, whose pharmacokinetics are not predicted by those of the parent compound, correlations between
cyclophosphamide pharmacokinetics and pharmacodynamics have not been demonstrated.
Cyclophosphamide is used in doses that range from 1.5 to 60 mg/kg/day. A steep dose-response curve exists, and reductions in dose can lead to unfavourable outcomes. Myelosuppression is the dose-limiting toxicity, although in the setting of
bone marrow transplantation, escalation beyond that dosage range is limited by
cardiac toxicity. Longer term complications of
cyclophosphamide therapy include
infertility and an increased incidence of
second malignancies. Cellular sensitivity to
cyclophosphamide is a function of cellular
thiol concentration, metabolism by
aldehyde dehydrogenases to form inactive metabolites, and the ability of
DNA to repair alkylated
nucleotides. Whether alteration of these cellular functions will lead to further improvements in clinical outcomes is an area of active investigation.