Repeated investigations of cyclophosphamide disposition in myeloma patients receiving intermittent chemotherapy.

Edwards, Glenn A.; Calvert, R. T.; Crowther, Derek; Bramwell, Vivien; Scarffe, J. H.

doi:10.1111/j.1365-2125.1980.tb01756.x

Cited by 12 publications

(4 citation statements)

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“…However, Bramwell et al found such wide individual variations in cyclophosphamide break-down that they could not establish a correlation between cyclophosphamide or alkylating metabolites and renal insufficiency. 3,4 They also showed that further metabolism before renal elimination was an important route of removal of alkylating activity. Grochow et al reviewed the clinical course of 120 myeloma patients receiving 60 mg/kg of CPA and failed to find any difference in hematologic toxicity between patients with normal and abnormal renal function.…”

Section: Discussionmentioning

confidence: 99%

“…However, little information is available about the pharmacokinetics of CPA in renal insufficiency. Bramwell et al reported that the alkylating activity of CPA is influenced more by the wide individual variation in CPA breakdown than by decreased renal function 3,4 and Grochow et al 5 failed to show any correlation between the severity of renal insufficiency and hematopoietic toxicity. Therefore, adjusting CPA doses in the presence of renal insufficiency has not been recommended.…”

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confidence: 99%

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Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure

Yamamoto

Kanda

Matsuyama

et al. 2000

Bone Marrow Transplant

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Summary:Cyclophosphamide (CPA) is widely used for peripheral blood stem cell mobilization, and a dose adjustment of CPA in the presence of renal failure has not been suggested. However, we describe a myeloma patient with renal failure (serum creatinine 4.2 mg/dl, creatinine clearance 11.2 ml/min) receiving CPA 2 g/m 2 for 2 days, who developed unexpectedly severe toxicity, including myopericarditis and prolonged myelosuppression. The serial serum concentrations of CPA metabolites were persistently much higher than those in a myeloma patient with normal renal function. We consider, therefore, that the dose of CPA should be reduced in the presence of severe renal failure when used as high-dose therapy or to mobilize peripheral blood stem cells. Bone Marrow Transplantation (2000) 26, 685-688. Keywords: cyclophosphamide; cardiotoxicity; pericardial effusion; renal failure; myeloma Multiple myeloma is a neoplastic disorder of plasma cells which is considered to be incurable with standard chemotherapy. 1 High-dose chemotherapy followed by hematopoietic stem cell support has resulted in prolonged event-free and overall survival. 2 However, eligibility criteria for highdose chemotherapy protocols generally require patients to have normal vital organ function. Impairment of renal function is one of frequent complications of multiple myeloma and affects the pharmacokinetics of variety of drugs.Cyclophosphamide (CPA) is one of the most useful antineoplastic agents also widely used for peripheral blood stem cell mobilization. However, little information is available about the pharmacokinetics of CPA in renal insufficiency. Bramwell et al reported that the alkylating activity of CPA is influenced more by the wide individual variation in CPA breakdown than by decreased renal function 3,4 and Grochow et al 5 failed to show any correlation between the severity of renal insufficiency and hematopoietic toxicity. Therefore, adjusting CPA doses in the presence of renal insufficiency has not been recommended. 5,6 However, we experienced a myeloma patient with renal failure, who received 4 g/m 2 of CPA for peripheral blood stem cell (PBSC) mobilization and eventually developed severe myopericarditis and prolonged myelosuppression. We present the clinical course and discuss the pharmacokinetics of CPA in renal failure. Case reportA 36-year-old woman with persistent fever was discovered to have Bence-Jones proteinuria, anemia and renal failure with a serum creatinine of 3.1 mg/dl, that rose to 6.5 mg/dl over 2 months. A skeletal survey demonstrated advanced osteolytic lesions. Bone marrow aspiration showed an increase in atypical plasma cells, thus establishing a diagnosis of multiple myeloma, stage IIIB, according to the criteria by Durie and Salmon. Two courses of VAD therapy (vincristine 0.4 mg/body for 4 days, doxorubicin 9 mg/m 2 for 4 days, dexamethazone 40 mg/body for days 1-4, 9-12 and 17-20) resulted in partial response and a decrease in serum creatinine level (from 6.5 mg/dl to 2.9 mg/dl). 7 Because of her young age and the f...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure

Yamamoto

Kanda

Matsuyama

et al. 2000

Bone Marrow Transplant

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“…Its metabolites are more highly protein bound, but none more than 67%. The calculated volume of distribution (V d) approximates total body water and has ranged from 0.54 to 1.1 L/kg in studies in humans (Edwards et al 1980;Grochow & Colvin 1983). In patients with multiple sclerosis treated with daily oral cyclophosphamide the concentrations in plasma and cerebrospinal fluid (CSF) were similar (Hommes et al 1983); patients with brain tumours receiving the drug intravenously exhibited peak CSF concentrations which were 50% of those in plasma.…”

Section: Distributionmentioning

confidence: 99%

Clinical Pharmacokinetics of Cyclophosphamide

Moore

1991

Clinical Pharmacokinetics

256

131

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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.

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“…Plasma halflife decreases with subsequent doses at both low (D'Incalci et al 1979) and high dose levels (Graham et al 1983;Sladek et al 1980) and the peak levels of alkylating activity in plasma also increased over a course (Bagley et al 1973). Edwards et al (1980) did not observe the same decrease in half-life but they did find an increase in clearance. In another study no change in pharmacokinetic parameters was noted after a 22-day course of low dose daily cyclophosphamide (Mouridsen et al 1976).…”

Section: Biotransformationmentioning

confidence: 47%

Pharmacokinetic Drug Interactions of Commonly Used Anticancer Drugs

Balis

1986

Clinical Pharmacokinetics

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With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacological characteristics of the anti-cancer drugs, such as steep dose-response curves, low therapeutic indices and severe toxicities, suggest that even small changes in the pharmacokinetic profile of the affected drug could significantly alter its toxicity or efficacy. In this review, drug interactions which quantitatively affect the absorption, distribution, biotransformation or excretion of the commonly used anticancer drugs are described. Most of the significant drug interactions involving this class of drugs occur at the level of biotransformation and excretion. For example, the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids, such as probenecid, salicylates and penicillin, which compete for tubular secretion, resulting in delayed clearance of methotrexate. The best described example of an interaction at the level of biotransformation is the effect of allopurinol on the catabolism of 6-mercaptopurine. By inhibiting xanthine oxidase, allopurinol blocks the first-pass metabolism of 6-mercaptopurine following its oral administration, leading to a 4- to 5-fold increase in plasma concentrations. Known drug interactions may potentially be used to enhance the antitumour activity of a drug--for instance, the administration of tetrahydrouridine (a cytidine deaminase inhibitor) with cytarabine in an attempt to block its rapid inactivation to uridine arabinoside. Overall, little information is available concerning the pharmacokinetic interactions of anticancer drugs with each other and with other classes of drugs in man, in part because the high incidence of toxicity and treatment failure, and empirical dosing methods, obscure the recognition of possible interactions. Awareness on the part of the clinician and more extensive pharmacokinetic investigation will be needed to recognise, document and avoid potentially harmful pharmacokinetic drug interactions involving this class of drugs.

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Repeated investigations of cyclophosphamide disposition in myeloma patients receiving intermittent chemotherapy.

Cited by 12 publications

References 9 publications

Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure

Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure

Clinical Pharmacokinetics of Cyclophosphamide

Pharmacokinetic Drug Interactions of Commonly Used Anticancer Drugs

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