Clinical Pharmacokinetics of Cyclophosphamide

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Cyclosphosphamide is widely used for cancer chemotherapy and for immunosuppression. The parent compound is inactive in vitro and exerts its biological activities through metabolites generated by hepatic microsomal enzymes. The drug may be administered either parenterally or orally. Systemic availability after oral administration is greater than 75% at the low doses which have been studied. Cyclophosphamide is minimally protein bound but some of its metabolites are more than 60% protein bound.

A linear 2-compartment model for the disposition of the parent compound has been formulated, but characteristics of the kinetics of disposition of the active metabolites have been delayed by analytical difficulties. Parameters vary widely between patients. Vc for this polar compound ranges from 0.32 to 0.34L/kg. Vd ranges from 0.60 to 0.64L/kg. T1/2β ranges from 3 to 12 hours.

Modelling of the time course of specific cytotoxic metabolites (aldophosphamide, 4-hydroxy-cyclophosphamide and phosphoramide mustard) has not been systematically performed. When measured by various nonspecific techniques, the serum concentration of metabolites was found to be maximal about 2 hours after an intravenous dose and declined by only 25% during the next 6 hours. Mean t1/2 was 7.7 hours in 1 study. Alkylating metabolites have been measured in the cerebrospinal fluid, but only a small fraction crosses the blood brain barrier.

At least 80% of an administered dose of cyclophosphamide is eliminated by metabolism. Both cyclophosphamide and metabolites are principally excreted by the kidney. Renal clearance has been measured at 5 to 11ml/min, suggesting extensive tubular resorption; up to 25% of the administered dose is excreted unchanged in the first 24 hours. Only 60% of radiolabel can be recovered in the urine over 24 to 48 hours. An additional 1 to 4% can be collected as expired CO2 or in the stool. Although elevated levels of metabolites have been described in patients with renal failure, a recent study did not demonstrate excess clinical toxicity in such patients. Unchanged cyclophosphamide has been shown to be extensively cleared by haemodialysis (78ml/min).

Complex interactions are to be expected with agents modifying hepatic microsomal activation, and conflicting data have been obtained in several animal studies. No clear alteration of the effects of cyclophosphamide has been observed in patients after phenobarbitone administration. Synergistic haematopoietic toxicity may occur with concomitant use of allopurinol.

Dose related efficacy has been demonstrated in animal models. Human data are available on dose related toxicity. One study demonstrated a direct relationship between metabolite AUC and depth of white blood count nadir. Clinical correlation between kinetic data and efficacy and/or toxicity awaits studies evaluating the time course of specific cytotoxic metabolites.

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