Clinical Pharmacokinetics of Cyclophosphamide

Abstract

Cyclophosphamide is an extensively used anticancer and immunosuppressive agent. It is a prodrug undergoing a complicated process of metabolic activation and inactivation. Technical difficulties in the accurate determination of the cyclophosphamide metabolites have long hampered the assessment of the clinical pharmacology of this drug. As these techniques are becoming increasingly available, adequate description of the pharmacokinetics of cyclophosphamide and its metabolites has become possible. There is incomplete understanding on the role of cyclophosphamide metabolites in the efficacy and toxicity of cyclophosphamide therapy. However, relationships between toxicity (cardiotoxicity, veno-occlusive disease) and exposure to cyclophosphamide and its metabolites have been established. Variations in the balance between metabolic activation and inactivation of cyclophosphamide owing to autoinduction, dose escalation, drug-drug interactions and individual differences have been reported, suggesting possibilities for optimisation of cyclophosphamide therapy. Knowledge of the pharmacokinetics of cyclophosphamide, and possibly monitoring the pharmacokinetics of cyclophosphamide in individuals, may be useful for improving its therapeutic index.

Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy

“…21 Cyclophosphamide is an alkylating nitrogen-mustard derivative capable of cross-linking intra-and interstrand DNA and DNA proteins, thereby inhibiting DNA replication and inducing apoptosis. 22 Adverse effects of cyclophosphamide such as haemorrhagic cystitis, cardiomyopathy, and hepatic veno-occlusion are well known, although the biologic mechanisms behind such effects are not completely understood. 22 However, few clinical studies have been conducted to examine the impact of specific chemotherapeutic agents on oral health outcomes in children.…”

“…22 Adverse effects of cyclophosphamide such as haemorrhagic cystitis, cardiomyopathy, and hepatic veno-occlusion are well known, although the biologic mechanisms behind such effects are not completely understood. 22 However, few clinical studies have been conducted to examine the impact of specific chemotherapeutic agents on oral health outcomes in children. 23,24 In our cohort of patients, we assessed the effect of antineoplastic therapy on dental development and salivary gland function in a cohort of recipients of childhood antineoplastic therapy.…”

High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy

“…In contrast to 4-hydroxycyclophosphamide, phosphoramide mustard cannot enter target cells, and therefore only the intracellularly formed phosphoramide mustard fraction is considered to be cytotoxic. Plasma concentrations of 4-hydroxycyclophosphamide are therefore a good marker of the alkylating activity of cyclophosphamide (De Jonge et al, 2005).…”

Analysis of 4-Hydroxycyclophosphamide in Cancer Patients Plasma for Therapeutic Drug Monitoring of Cyclophosphamide

“…Phosphoramide mustard will react with DNA and form cross-link through covalent bonding, whether intrastrand or interstrand, both can inhibit DNA replication so that the cell will go through apoptosis and die. CYP3A4 and CYP2B6 catalyzed the reaction for 4-OHCP formation [5][6][7][8].…”