Decreased plasma half-life of cyclophosphamide during repeated high-dose administration

Graham, M.I.; Shaw, Ian C.; Souhami, R. L.; Sidau, B.; Harper, P.; McLean, A. E. M.

doi:10.1007/bf00255760

Cited by 45 publications

(23 citation statements)

References 6 publications

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“…The terminal elimination half-life of ifosfamide at this dose was similar to that for low dose cyclophosphamide (5.1 h) (Graham et al, 1983). The plasma decay of unchanged ifosfamide at this dose was best fitted by a monoexponential function, as shown by others (Creaven et al, 1976;Nelson et al, 1976 Our findings are similar to that of Lind et al (1989) using 1.5 g m2 ifosfamide intravenously daily for 5 days who found an increase in ifosfamide clearance from a median of 69.19 ml min -1 on day 1 to a median of 123.19 ml min -1 on day 5 without a change in ifosfamide distribution.…”

supporting

confidence: 59%

Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Lewis

Fitzgerald

Harper

et al. 1990

Brit J Clinical Pharma

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1 Fifteen patients received 1.5 g m-2 of ifosfamide intravenously over 0.5 h every day for 5 days. Twenty-one courses of treatment were studied. Plasma was assayed for ifosfamide by gas liquid chromatography and plasma alkylating activity was measured using the nitrobenzylpyridine (NBP) reaction. 2 A pharmacokinetic analysis revealed a significant decrease in the median (range) elimination half-life of ifosfamide from 7.2 (2.8-14.2) h on day 1 to 4.6 (2.3-7.7) h on day 5 (P < 0.001, Wilcoxon's test) with a concomitant significant increase in the median (range) clearance from 66 (31-148) ml min-1 on day 1 to 115 (52-381) ml min-' on day 5 (P < 0.001). There was no significant change in the volume of distribution on day 5 compared with day 1.3 There was a highly significant 223% increase in the median (range) plasma nitrobenzylpyridine alkylating activity area under the curve on day 1 from 16 (0.6-105) nmol nor nitrogen mustard equivalents ml-' h to 52 (13-238) nmol nor nitrogen mustard equivalents ml-' h on day 5. 4 During five courses of treatment (in five patients in the group) 24 h urine samples were collected on days 1 and 5. The median (range) renal clearance of ifosfamide on day 1 was 6.8 (1.3-16.2) ml min-1 compared with 5.7 (1.3-15.3) ml min-1 on day 5. This difference was not significant. The median (range) metabolic clearance of ifosfamide in these five patients on day 1 was 78.6 (39.9-141.2) ml min-1 and 132.6 (54.6-149.5) ml min on day 5. This difference in metabolic clearance did not reach statistical significance. 5 These data indicate that after 5 days fractionated intravenous ifosfamide at 1.5 g m daily produces a time-dependent increase in ifosfamide metabolism.

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supporting

confidence: 59%

Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Lewis

Fitzgerald

Harper

et al. 1990

Brit J Clinical Pharma

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“…The lower values of CY concentrations and the half-lives on the second day of treatment are due to the self-induction of CY metabolism as already described. [12][13][14][15] In conclusion, hemodialysis might be useful in removing metabolites of cyclophosphamide in patients with renal dysfunction receiving high-dose chemotherapy. 16 This report indicates that patients with severe renal failure may receive intensive myeloablative therapy with unrelated BMT without major adverse clinical events.…”

Section: Discussionmentioning

confidence: 99%

Total body irradiation and cyclophosphamide is a conditioning regimen for unrelated bone marrow transplantation in a patient with chronic myelogenous leukemia and renal failure on hemodialysis

Bischoff

Blau

Wagner

et al. 1998

Bone Marrow Transplant

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Summary:Five years after the diagnosis of Ph chromosome-positive chronic myeloid leukemia (CML) a 31-year-old patient developed malignant nephrosclerosis with renal failure. He then underwent an allogeneic unrelated BMT in first chronic phase CML. The preparative regimen consisted of fractionated total body irradiation (TBI) and cyclophosphamide (CY). We studied the pharmacokinetics of cyclophosphamide on hemodialysis and compared clinical parameters including time to engraftment and toxicity with parameters of a patient with normal renal function who also received an unrelated marrow as treatment for CML in first chronic phase. Our results suggest that TBI/CY is a suitable conditioning regimen for allogeneic transplantation in patients with hematological malignancy and renal failure on hemodialysis. Keywords: bone marrow transplantation; renal failure; cyclophosphamide; total body irradiation; pharmacokinetics; hemodialysis Matched unrelated donor (MUD) transplantation is the best available treatment for young patients with CML in chronic or accelerated phase without a matched sibling donor. 1-3However, a serious therapeutic problem for BMT is hemodialysis-dependent renal insufficiency. An important question in this clinical setting relates to the optimal conditioning regimen to ensure an adequate myelosuppression in patients with disturbed renal function on hemodialysis. There is concern with regard to the tolerance of intensive chemotherapy in hematological patients with severe renal failure. 4 The aim of our report is to show that a conditioning regimen with TBI and CY can be used successfully in a patient with CML and severe renal insufficiency requiring hemodialysis. Patients and methodsA 31-year-old patient with Ph+ CML (patient A) was treated with a combination of alpha-interferon and hydroxyurea for 5 years and with hydroxyurea alone for the last 6 months before admission to our department. A MUD transplantation was offered to the patient according to the recommendations of the Consensus Panel chaired by EC Gordon Smith stating that for patients with CML in chronic phase or accelerated phase, unrelated donor BMT should be considered as the best available treatment at present for patients without a matched sibling donor.2 The patient developed malignant nephrosclerosis and was hemodialysis-dependent on admission. The data were compared to the data in a matched pair patient (patient B) with similar clinical characteristics conditioned with the same regimen ( Table 1). The conditioning regimen for BMT consisted of TBI with a total dose of 13.5 Gy from days Ϫ6 to Ϫ4 and CY 60 mg/kg once daily i.v. on days Ϫ3 and Ϫ2 (total dose 120 mg/kg).CY concentration was determined in serum and dialysate of patient A, and in serum and urine of patient B. Hemodialysis was performed in patient A 6 h after each CY infusion over a period of 6 h on days Ϫ3 and Ϫ2. The patient received, in addition, a bladder irrigation, 5 and a continuous i.v. infusion of mesna 60 mg/kg body weight/24 h on days Ϫ3 and Ϫ2. Patient B received...

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“…It had been reported that plasma half-life of cyclo in patients decreased both during repeated high dose administration (50 mg kg-I day-I for 4 successive days) and under continual low dose treatment of cyclo (100mg day-1 for over 1 year) (D'Incalci et al, 1979;Graham et al, 1983). One possible mechanism is that multiple doses of cyclo have an inducing effect on enzymes involved in the metabolism of cyclo, although in another clinical study, no change in cyclo metabolism was found in patients after 22 days of treatment with daily doses of 2mgkg-1 (Mouridsen et al, 1976).…”

Section: Discussionmentioning

confidence: 99%

“…In three clinical studies, the plasma half-life of cyclophosphamide decreased both after repeated low-dose and high-dose treatments (D'Incalci et al, 1979;Graham et al, 1983;Sladek et al, 1984). This was probably due to cyclophosphamide having an inducing effect on enzymes responsible for its metabolism, leading to an increased rate of disappearance of its metabolites from plasma.…”

mentioning

confidence: 99%

Tumour response to chemotherapy in animals that have been treated with the same drugs prior to tumour implantation: A model for studying host effects on apparent drug resistance

Luk

Tannock²

1988

Br J Cancer

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Summary The outcome of cancer chemotherapy is determined by an interplay of multiple factors between the host, the tumour, and the drugs administered. Most studies have emphasised the development or selection of drug resistant tumour cells. However, repeated drug treatment of the host may lead to changes (e.g. in pharmacokinetics, host defences, etc.) which can influence the subsequent response of the tumour. In this study, we present a model to investigate the role of the host in the development of drug resistance. A drug is administered repeatedly to animals prior to tumour implantation, and tumour response is then evaluated following treatment with the same drug in pretreated and control animals.To illustrate the method, cyclophosphamide was administered weekly for 4 weeks to C3H mice before implantation of the KHT tumour. Tumour growth delay was then compared after one further treatment of cyclophosphamide in this group of animals to that in control mice which had not received the cyclophosphamide pretreatment. Our results indicate that cyclophosphamide produces only a small effect on the host in this system, but the model is a potentially useful one to investigate the contribution of the host in the acquisition of drug resistance.

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Decreased plasma half-life of cyclophosphamide during repeated high-dose administration

Cited by 45 publications

References 6 publications

Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Total body irradiation and cyclophosphamide is a conditioning regimen for unrelated bone marrow transplantation in a patient with chronic myelogenous leukemia and renal failure on hemodialysis

Tumour response to chemotherapy in animals that have been treated with the same drugs prior to tumour implantation: A model for studying host effects on apparent drug resistance

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