Source: FDA, National Drug Code (US) Revision Year: 2020
Busulfan is a small, highly lipophilic molecule that easily crosses the blood brain barrier. Following absorption, 32% and 47% of busulfan are bound to plasma proteins and red blood cells, respectively.
Busulfan absorption from the gastrointestinal tract is essentially complete. This has been demonstrated in radioactive studies after both intravenous and oral administration of 35S-busulfan, 14C-busulfan, and 3H-busulfan. Following intravenous administration of a single therapeutic dose of 35S-busulfan, there was rapid disappearance of radioactivity from the blood and 90% to 95% of the 35S-label disappeared within 3 to 5 minutes after injection. After either oral or intravenous administration of 35S-busulfan, 45% to 60% of the radioactivity was recovered in the urine in the 48 hours after administration; the majority of the total urinary excretion occurring in the first 24 hours. Over 95% of the urinary 35S-label occurs as 35S-methanesulfonic acid. Oral and intravenous administration of 1,4-14C-busulfan showed the same rapid initial disappearance of plasma radioactivity as observed following the administration of 35S-labeled drug. Cumulative radioactivity in the urine after 48 hours was 25% to 30% of the administered dose (contrasting with 45% to 60% for 35S-busulfan), and suggests a slower excretion of the alkylating portion of the molecule and its metabolites than for the sulfonoxymethyl moieties. Regardless of the route of administration, 1,4-14C-busulfan yielded a complex mixture of at least 12 radiolabeled metabolites in urine; the main metabolite being 3-hydroxytetrahydrothiophene-1,1-dioxide. Pharmacokinetic studies employing 3H-busulfan labeled on the tetramethylene chain confirmed a rapid initial clearance of the radioactivity from plasma, irrespective of whether the drug was given orally or intravenously.
A study compared a 2-mg single IV bolus injection to a single oral dose of a 2-mg tablet of nonradioactive busulfan in 8 adult patients 13 to 60 years of age. The study demonstrated that the mean ± SD absolute bioavailability was 80% ± 20% in adults. However, the absolute bioavailability for 8 children 1.5 to 6 years of age was 68% ± 31%.
In another study of 2, 4, and 6 mg of busulfan, given as a single oral dose on consecutive days (starting with the lowest dose) in 5 adult patients, the mean dose-normalized (to 2 mg dose) area under the plasma concentration-time curve (AUC) was about 130 ng•hr/mL, while the mean intra- and inter-patient variability was about 16% and 21%, respectively. Busulfan was eliminated with a plasma terminal elimination half-life (t1/2) of about 2.6 hours, and demonstrated linear kinetics within the range of 2 to 6 mg for both the maximum plasma concentration (Cmax) and AUC. The mean Cmax for the 2-, 4-, and 6-mg doses (after dose normalization to 2 mg) was about 30 ng/mL. A recent study of 4 to 8 mg as single oral doses in 12 patients showed that the mean ± SD Cmax (after dose normalization to 4 mg) was 68.2 ± 24.4 ng/mL, occurring at about 0.9 hours and the mean ± SD AUC (after dose normalization to 4 mg) was 269 ± 62 ng•hr/mL. These results are consistent with previous results. In addition, the mean ± SD elimination half-life was 2.69 ± 0.49 hours.
The elimination of busulfan appears to be independent of renal function. This probably reflects the extensive metabolism of the drug in the liver, since less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. The drug is metabolized by enzymatic activity to at least 12 metabolites, among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity.
There is no experience with the use of dialysis in an attempt to modify the clinical toxicity of busulfan. One technical difficulty would derive from the extremely poor water solubility of busulfan. Additionally, all studies of the metabolism of busulfan employing radiolabeled materials indicate rapid chemical reactivity of the parent compound with prolonged retention of some of the metabolites (particularly the metabolites arising from the “alkylating” portion of the molecule). The effectiveness of dialysis at removing significant quantities of unreacted drug would be expected to be minimal in such a situation.
Currently, there are no available data on the effect of food on busulfan bioavailability.
The impact of hemodialysis on the clearance of busulfan was determined in a patient with chronic renal failure undergoing autologous stem cell transplantation. The apparent oral clearance of busulfan during a 4-hour hemodialysis session was increased by 65%, but the 24-hour oral clearance of busulfan was increased by only 11%.
The incidence of veno-occlusive disease was higher (33.3% versus 3.0%) in patients with busulfan AUC0-6hr >1,500 μM.min (Css >900 mcg/L) compared to patients with busulfan AUC0-6hr <1,500 μM.min (Css <900 mcg/L) (see WARNINGS).
Itraconazole reduced busulfan clearance by up to 25% in patients receiving itraconazole compared to patients who did not receive itraconazole. Higher busulfan exposure due to concomitant itraconazole could lead to toxic plasma levels in some patients. Fluconazole had no effect on the clearance of busulfan. Patients treated with concomitant cyclophosphamide and busulfan with phenytoin pretreatment have increased cyclophosphamide and busulfan clearance, which may lead to decreased concentrations of both cyclophosphamide and busulfan. However, busulfan clearance may be reduced in the presence of cyclophosphamide alone, presumably due to competition for glutathione.
Diazepam had no effect on the clearance of busulfan.
No information is available regarding the penetration of busulfan into brain or cerebrospinal fluid.
In aqueous media, busulfan undergoes a wide range of nucleophilic substitution reactions. While this chemical reactivity is relatively non-specific, alkylation of the DNA is felt to be an important biological mechanism for its cytotoxic effect. Coliphage T7 exposed to busulfan was found to have the DNA crosslinked by intrastrand crosslinkages, but no interstrand linkages were found.
The metabolic fate of busulfan has been studied in rats and humans using 14C- and 35S-labeled materials. In humans, as in the rat, almost all of the radioactivity in 35S-labeled busulfan is excreted in the urine in the form of 35S-methanesulfonic acid. Roberts and Warwick demonstrated that the formation of methanesulfonic acid in vivo in the rat is not due to a simple hydrolysis of busulfan to 1,4-butanediol, since only about 4% of 2,3-14C-busulfan was excreted as carbon dioxide, whereas 2,3-14C-1,4-butanediol was converted almost exclusively to carbon dioxide. The predominant reaction of busulfan in the rat is the alkylation of sulfhydryl groups (particularly cysteine and cysteine-containing compounds) to produce a cyclic sulfonium compound which is the precursor of the major urinary metabolite of the 4-carbon portion of the molecule, 3-hydroxytetrahydrothiophene-1,1-dioxide. This has been termed a “sulfur-stripping” action of busulfan and it may modify the function of certain sulfur-containing amino acids, polypeptides, and proteins; whether this action makes an important contribution to the cytotoxicity of busulfan is unknown.
The biochemical basis for acquired resistance to busulfan is largely a matter of speculation. Although altered transport of busulfan into the cell is one possibility, increased intracellular inactivation of the drug before it reaches the DNA is also possible. Experiments with other alkylating agents have shown that resistance to this class of compounds may reflect an acquired ability of the resistant cell to repair alkylation damage more effectively.
Although not curative, busulfan reduces the total granulocyte mass, relieves symptoms of the disease, and improves the clinical state of the patient. Approximately 90% of adults with previously untreated chronic myelogenous leukemia will obtain hematologic remission with regression or stabilization of organomegaly following the use of busulfan. It has been shown to be superior to splenic irradiation with respect to survival times and maintenance of hemoglobin levels, and to be equivalent to irradiation at controlling splenomegaly.
It is not clear whether busulfan unequivocally prolongs the survival of responding patients beyond the 31 months experienced by an untreated group of historical controls. Median survival figures of 31 to 42 months have been reported for several groups of patients treated with busulfan, but concurrent control groups of comparable, untreated patients are not available. The median survival figures reported from different studies will be influenced by the percentage of “poor risk” patients initially entered into the particular study. Patients who are alive 2 years following the diagnosis of chronic myelogenous leukemia, and who have been treated during that period with busulfan, are estimated to have a mean annual mortality rate during the second to fifth year which is approximately two thirds that of patients who received either no treatment, conventional x-ray or 32P-irradiation, or chemotherapy with minimally active drugs.
Busulfan is clearly less effective in patients with chronic myelogenous leukemia who lack the Philadelphia (Ph1) chromosome. Also, the so-called “juvenile” type of chronic myelogenous leukemia, typically occurring in young children and associated with the absence of a Philadelphia chromosome, responds poorly to busulfan. The drug is of no benefit in patients whose chronic myelogenous leukemia has entered a “blastic” phase.
MYLERAN should not be used in patients whose chronic myelogenous leukemia has demonstrated prior resistance to this drug.
MYLERAN is of no value in chronic lymphocytic leukemia, acute leukemia, or in the “blastic crisis” of chronic myelogenous leukemia.
See WARNINGS section. The World Health Organization has concluded that there is a causal relationship between busulfan exposure and the development of secondary malignancies.
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