Busulfan

Busulfan is a useful, sufficiently safe drug in the treatment of patients with CML. At higher dosages, busulfan is a fundamental part of myeloablative therapies for patients undergoing BMT. As the pharmacokinetics and metabolism of busulfan is further understood, there is great potential for improving treatment outcome. An assessment of maximal tolerated exposure determined by therapeutic drug monitoring may decrease the incidence and lethality of regimen-related toxicities

Evaluation of two buflomedil tablet formulations in patients with atherosclerotic disease.

The bioequivalence of a 600-mg methocel tablet containing buflomedil hydrochloride in sustained-release form was determined relative to a 300-mg CAP/carbovax-coated tablet of buflomedil hydrochloride in immediate-release form. The tablets were given to 20 patients in a double-blind placebo- controlled clinical study with cross-over between the administration plans. The 300-mg tablets were given b.i.d., at 8 a.m. and 8 p.m. while the 600-mg tablets were taken once a day at 8 a.m. (+placebo at 8 p.m.). Plasma samples were collected at appropriate times up to 24 h after administration and were analysed for buflomedil with a validated high-performance liquid chromatographic procedure. Results showed an overall significant mean difference in absorption rate between the two formulations. The mean t(max) (5.5 \ub1 3.5 h) for the 600-mg tablet was longer (P<0.001) than the t(max) value (1.8 \ub1 0.8 h) seen after administration of the first 300-mg tablet. Analysis of AUC((O- 1e)) values indicated that the sustained-release preparation (32.1 \ub1 20.7 \u3bcg/ml h) was not significantly different from the 300-mg tablet b.i.d. (28.7 \ub1 16.0 \u3bcg/ml h). Furthermore, it was seen that single administration of a 600-mg sustained-release tablet of buflomedil hydrochloride delivered the same amount of total drug as a 300-mg tablet given twice a day

Disposition of high dose busulfan in pediatric patients undergoing bone marrow transplantation

We studied the pharmacokinetics of busulfan (16 mg/kg) in 16 pediatric patients affected by malignant and nonmalignant disorders between 6 months and 19 years of age (mean ± SD, 5.7 ± 6.5 years) who were undergoing allogeneic (15 patients) and autologous (one patient) bone marrow transplantation. In all children, the conditioning regimen consisted of busulfan given orally at a dose of 1 mg/kg every 6 hours for 16 doses (total dose, 16 mg/kg), associated with other drugs. The pharmacokinetics of busulfan was studied during the 6‐hour dosing interval on the third day of therapy by use of a high‐performance liquid chromatographie assay. The value for the time to reach maximum concentration, expressed as mean ± SD, was 1.1 ± 0.5 hour; maximum concentration was 609.6 ± 225.3 ng/ml; steady‐state concentration was 358.9 ± 135.5 ng/ml; area under the plasma concentration–time curve was 2153.6 ± 813.1 ng · hr/ml; oral clearance was 0.535 ± 0.226 L/hr/kg; and half‐life was 2.4 ± 0.8 hours. Age‐related differences in busulfan disposition were observed. The mean busulfan oral clearance in a group of 10 patients with an age range from 6 months to 3 years was 0.619 L/hr/kg, whereas six patients whose ages ranged from 7 to 19 years had a oral clearance of 0.396 L/hr/kg. The half‐lives for busulfan during infancy decrease continuously until early childhood but were prolonged in older children. No significant relationship between systemic exposure to busulfan and drug effect was observed. Clinical Pharmacology and Therapeutics (1993) 54, 45–52; doi: © 1993 American Society for Clinical Pharmacology and Therapeutic

Disposition of high‐dose busulfan in pediatric patients undergoing bone marrow transplantation

We studied the pharmacokinetics of busulfan (16 mg/kg) in 16 pediatric patients affected by malignant and nonmalignant disorders between 6 months and 19 years of age (mean ± SD, 5.7 ± 6.5 years) who were undergoing allogeneic (15 patients) and autologous (one patient) bone marrow transplantation. In all children, the conditioning regimen consisted of busulfan given orally at a dose of 1 mg/kg every 6 hours for 16 doses (total dose, 16 mg/kg), associated with other drugs. The pharmacokinetics of busulfan was studied during the 6‐hour dosing interval on the third day of therapy by use of a high‐performance liquid chromatographie assay. The value for the time to reach maximum concentration, expressed as mean ± SD, was 1.1 ± 0.5 hour; maximum concentration was 609.6 ± 225.3 ng/ml; steady‐state concentration was 358.9 ± 135.5 ng/ml; area under the plasma concentration–time curve was 2153.6 ± 813.1 ng · hr/ml; oral clearance was 0.535 ± 0.226 L/hr/kg; and half‐life was 2.4 ± 0.8 hours. Age‐related differences in busulfan disposition were observed. The mean busulfan oral clearance in a group of 10 patients with an age range from 6 months to 3 years was 0.619 L/hr/kg, whereas six patients whose ages ranged from 7 to 19 years had a oral clearance of 0.396 L/hr/kg. The half‐lives for busulfan during infancy decrease continuously until early childhood but were prolonged in older children. No significant relationship between systemic exposure to busulfan and drug effect was observed. Clinical Pharmacology and Therapeutics (1993) 54, 45–52; doi: © 1993 American Society for Clinical Pharmacology and Therapeutic

Nitrite and nitrate plasma levels, as markers for nitric oxide synthesis, in thrombotic thrombocytopenic purpura (TTP). A case-control study

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Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation

Busulfan (BU) is an alkylating drug frequently used to prepare patients for bone marrow transplantation (BMT). Several studies have documented that there is important interpatient variability in BU disposition and systemic exposure, and that other drugs with a common metabolic pathway are capable of influencing BU clearance. We compared the BU pharmacokinetics and pharmacodynamics of 13 patients given BMT and receiving BU and itraconazole, with those of 26 matched controls who did not receive any anti-fungal agent, and with those of 13 matched patients treated with fluconazole as prophylaxis against fungal infections. The effect of itraconazole was best reflected in BU clearance since the BU dose was modified in some patients. BU clearance was decreased by an average of 20% in patients receiving itraconazole as compared to control patients and patients receiving fluconazole (p &lt; 0.01). Mean BU clearance was 7.653 ± 1.871 l/hr.m2 in the itraconazole patients, 10.103 ± 2.007 l/hr.m2 in the itraconazole group and 9.373 ± 1.702 l/hr.m2 in the control group. In this study itraconazole, but not fluconazole, markedly affected the pharmacokinetics of BU as an increase of BU plasma concentrations was observed. The nature of this interaction has not yet been fully characterized. Itraconazole and its analogues are inhibitors of both cytochrome P450 and lipoxygenase and since itraconazole can modulate BU pharmacokinetics, oxidative catabolism is probably a determinant of BU metabolism. This hypothesis should be tested in human metabolic studies

Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation

Busulfan (BU) is an alkylating drug frequently used to prepare patients for bone marrow transplantation (BMT). Several studies have documented that there is important interpatient variability in BU disposition and systemic exposure, and that other drugs with a common metabolic pathway are capable of influencing BU clearance. We compared the BU pharmacokinetics and pharmacodynamics of 13 patients given BMT and receiving BU and itraconazole, with those of 26 matched controls who did not receive any anti-fungal agent, and with those of 13 matched patients treated with fluconazole as prophylaxis against fungal infections. The effect of itraconazole was best reflected in BU clearance since the BU dose was modified in some patients. BU clearance was decreased by an average of 20% in patients receiving itraconazole as compared to control patients and patients receiving fluconazole (p < 0.01). Mean BU clearance was 7.653 +/- 1.871 l/hr.m2 in the itraconazole patients, 10.103 +/- 2.007 l/hr.m2 in the fluconazole group and 9.373 +/- 1.702 l/hr.m2 in the control group. In this study itraconazole, but not fluconazole, markedly affected the pharmacokinetics of BU as an increase of BU plasma concentrations was observed. The nature of this interaction has not yet been fully characterized. Itraconazole and its analogues are inhibitors of both cytochrome P450 and lipoxygenase and since itraconazole can modulate BU pharmacokinetics, oxidative catabolism is probably a determinant of BU metabolism. This hypothesis should be tested in human metabolic studies