Clinical Pharmacokinetics of Cyclophosphamide

Abstract

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.

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

“…Genetic and environmental factors as well as comedications that affect cytochrome P450 activity are known to modify the antitumor effects of MTD (20) and, potentially also, LDM CPA. Interestingly, CPA in high doses is capable of inducing its own activation, which is mediated at least partially by cytochrome P 450 isoform 3A4 (CYP3A4) induction (21). CYP3A4 is also involved in a competing side chain oxidation of CPA, which results in N-dechloroethylation and the formation of the neurotoxic metabolite chloroacetaldehyde (18).…”

The role of plerixafor in optimizing peripheral blood stem cell mobilization for autologous stem cell transplantation

“…8,[15][16][17][18] A steep dose-response curve exists for cyclophosphamide, with myelosuppression being the dose-limiting factor. 19 Chemomobilization in combination with G-CSF is often disease specific and may eliminate the need for separate mobilization therapy following induction or salvage treatment. In lymphoma, salvage chemotherapy regimens such as IVE (ifosfamide, vincristine, etoposide), IEV (ifosfamide, epirubicin, etoposide), ICE (ifosfamide, carboplatin, etoposide) or DHAP (cytarabine, cisplatin, dexamethasone) are frequently used to both reduce tumor burden and enhance stem cell mobilization.…”

The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity

“…8,9 CP is an alkylating prodrug, mainly metabolized to active and inactive metabolites via cytochrome P450 in the liver. 10,11 The cytotoxic effect is produced by the active metabolites, 4-hydroxycyclophosphamide (4-OHCP) and phosphoramide mustard (PM). The inactive metabolite monochloroethyl-cyclophosphamide (DCCP) is produced by a separate oxidative N-dealkylation reaction.…”