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PubMed2003

N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of busulfan during conditioning prior to allogeneic stem cell transplantation.

Busulfan is currently used as a main component in the conditioning regimen prior to allogeneic stem cell transplantation (SCT). Several studies have shown a correlation between exposure to busulfan and transplantation-related liver toxicity, such as venoocclusive disease (VOD) in patients undergoing SCT. Busulfan is metabolized mainly through glutathione (GSH). During high-dose therapy, busulfan may deplete hepatocellular levels of GSH. As part of the conditioning therapy, busulfan is usually followed by high doses of cyclophosphamide. The activation of cyclophosphamide yields a cytotoxic metabolite, 4-hydroxy cyclophosphamide, which is highly reactive and detoxified through GSH. According to recent studies using cell lines and animal models N-acetyl-L-cysteine (NAC), a GSH precursor, does not hamper the myeloablative effect of busulfan during conditioning. In the present study, we administered NAC during conditioning to 10 patients at risk of VOD due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC infusions were observed and busulfan concentrations were not affected. All patients became pancytopenic and engrafted with 100% donor cells. None of the patients developed VOD or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggest that NAC therapy is safe and does not impair the myeloablative effect of busulfan during conditioning prior to SCT.

Acetylcysteine↗
PubMed2005

Accidental busulfan overdose during conditioning for stem cell transplantation.

High dose busulfan is widely used in preparative regimens for bone marrow transplantation. We describe three cases of accidental busulfan overdosing. Two adults received a single dose of 8 and 18 mg/kg busulfan, respectively. Doses of 9 x 4 mg/kg were ingested by a 14-year-old girl, who experienced seizures. In all cases, no severe liver toxicity including veno-occlusive disease was observed. Plasma samples were obtained from two patients. Busulfan plasma concentrations were far above published values after high-dose busulfan treatment. Busulfan was eliminated by a first-order process. All patients survived these high doses of busulfan and successful transplantation was possible. Two patients died from refractory GvHD on days 91 and 80 after transplantation. One patient is alive in remission after an observation time of 18 months. These cases show that busulfan overdosing may occur and pharmacokinetic evaluation is warranted to estimate risk of early and late toxicity.

Adolescent↗
PubMed2000

A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation.

Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.

Acute Disease↗
PubMed2002

Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation.

AIMS: Intravenous formulations of busulfan have recently become available. Although busulfan is used frequently in children as part of a myeloablative regimen prior to bone marrow transplantation, pharmacokinetic data on intravenous busulfan in children are scarce. The aim was to investigate intravenous busulfan pharmacokinetics in children and to suggest a limited sampling strategy in order to determine busulfan systemic exposure with the minimum of inconvenience and risk for the patient. METHODS: Plasma pharmacokinetics after the first administration was investigated in six children using nonlinear mixed effect modelling. RESULTS: Pharmacokinetics showed little variability and were described adequately with a one-compartment model (population estimates CL,av=0.29 l h(-1) kg(-1); V,av=0.84 l kg(-1); t(1/2)=1.7-2.8 h). Combined with limited sampling and a Bayesian fitting procedure, the model can adequately estimate the systemic exposure to intravenous busulfan, which in children appears to be at the lower end of the adult range. CONCLUSIONS: Busulfan systemic exposure in children during intravenous administration can be estimated adequately with limited sampling and a Bayesian fitting procedure from a one-compartment model. Intravenous busulfan pharmacokinetics in children should be the subject of more research.

Adolescent↗
PubMed2002

A limited sampling strategy for pharmacokinetic directed therapy with intravenous busulfan.

High-dose busulfan is widely used in allogeneic and autologous marrow transplantation preparative regimens. Variation in the area under the concentration/time curve (AUC) for oral busulfan results in substantial risk of over or under treatment with excess risk of toxicity or relapse. Use of the IV formulation reduces this variability by eliminating variability in absorption. Variability due to drug metabolism remains, but simplified pharmacokinetic study may be employed to achieve a specific target AUC. In conventional sampling strategies for determining AUC after oral administration, 12 samples are used over 6 hours to assure accurate tracking of erratic absorption. With IV busulfan there is no necessity for measuring plasma levels during the infusion because busulfan pharmacokinetics are well described with a single-compartment, first-order elimination model. In theory, only peak and trough levels should be necessary, but for assurance of reliability in clinical decision making, it must be possible to identify outlier values. This process requires at least 4 samples. We studied a total of 59 adult patients receiving a 2-hour IV busulfan infusion to develop a limited sampling strategy (LSS). At the end of a 2-hour infusion, we collected 11 samples from 18 patients and compared the AUC obtained when all samples were used with the AUC obtained when samples were collected only hourly. The mean AUC calculation was 5% higher (1002 versus 956 microM-min) and the coefficient of variation (CV) was substantially better (4.6% versus 8.2%) when only the postinfusion samples were used. A follow-up study of 41 consecutive patients demonstrated that all patients were easily evaluable with a coefficient of variation (CV) for the AUC of 2.6%. To validate this approach, we analyzed pharmacokinetic data on 60 patients in the phase II clinical trial of the IV formulation described by Anderson et al. Data on an additional 36 patients from a companion study also were analyzed. The AUC based on all 11 samples from each patient were compared with the AUC based on the 5 postinfusion samples. The results of this analysis confirmed comparable reliability and possibly superior precision of the University of Alabama at Birmingham 5-sample LSS. These results validated that LSS for IV busulfan will make possible meaningful and accurate comparisons of busulfan versus TBI-based preparative regimens and comparison of dose intensity of busulfan-containing preparative regimens in trials of submyeloablative transplantation.

Antineoplastic Agents, Alkylating↗
PubMed1981

Busulfan, antimetabolites, radiotherapy, and cost of treatment in chronic myelocytic leukemia. A non-controlled, non-randomized monocenter study with historical controls.

The possibilities were studied of achieving remission more quickly, of preventing conceivably alkylator-induced blastic transformation, and of prolonging survival in chronic myelocytic leukemia (CML) by replacing busulfan induction of remission by antimetabolite induction. The promise of the project was not considered to merit a prospective, controlled, randomized multicenter study, and therefore a retrospective, non-controlled, non-randomized pilot study was elected. One antimetabolite-treated group (cytosine arabinoside and thioguanine) and two busulfan-treated patient groups were studied. One of the latter two groups received splenic irradiation in addition to busulfan. No statistically significant differences between the busulfan groups were found in the time to achieve remission, the length of the first, unmaintained remission, the frequency of blastic metamorphosis or the cost of treatment. The actuarial survival curves of all three groups were similar. The antimetabolite induction was well tolerated and led to a statistically significantly more rapid remission than busulfan. However, the remission was significantly shorter, and no significant difference in the frequency of blastic metamorphosis was found between the groups. The median cost (from diagnosis to death) of hospitalization, visits, treatment, and part of the loss of production was approximately 106 000 Sw. cr. in the busulfan + radiotherapy group, 116 000 in the busulfan group, and 178 000 in the antimetabolite group. It is suggested that a prospective, randomized, controlled study could confirm that the present antimetabolite induction may lead to a more rapid remission induction in CML without more side-effects. However, to prevent early relapse, antimetabolite induction should be combined with busulfan maintenance treatment.

Busulfan↗
PubMed2006

Quantification of busulfan in saliva and plasma in haematopoietic stem cell transplantation in children : validation of liquid chromatography tandem mass spectrometry method.

BACKGROUND AND OBJECTIVE: Busulfan pharmacokinetic studies suggest that an individual dosing strategy may be necessary to optimise systemic exposure in order to decrease toxicity and improve outcome in haematopoietic stem cell transplantation. Therapeutic and toxic effects of the busulfan/cyclophosphamide regimen have been related to the area under the busulfan plasma concentration-time curve. Because of practical limitations in obtaining blood from children, saliva was evaluated as an alternative matrix for therapeutic drug monitoring, offering the advantages of a non-invasive, rapid and easy sampling procedure. Another objective was to evaluate an easy and robust liquid chromatography- tandem mass spectrometry method for plasma and saliva busulfan determination. METHODS: An online extraction cartridge with column-switching technique, analytical liquid chromatography over a Chromolith RP 18 e column, and tandem mass spectrometry were used to quantify busulfan concentrations in matched plasma and saliva samples. The study population consisted of ten patients, aged 1.3-19 years (median age 11.8 years, seven females, three males), undergoing haematopoietic stem cell transplantation. All patients received busulfan 0.8-1.3 mg/kg orally every 6 hours for a total of 16 doses, followed by two doses of cyclophosphamide (60 mg/kg/day). RESULTS: The lowest limit of detection was 2 microg/L and the lower limit of quantification was 10 microg/L. Only 100 microL of plasma/saliva was needed. The mean recoveries (SD) of busulfan were 97.2% (2.7) in plasma and 100.4% (1.3) in saliva. Intra- and inter-assay imprecision was 2-3% and 2-4% for plasma, and 1-2% and 2-4% for saliva (concentration range 30-1,500 microg/L). The bias was <4% for both plasma and saliva. The correlation between the busulfan concentration in plasma and saliva was highly significant (r=0.958; p<0.0001; saliva/plasma ratio=1.09+/-0.04; n=69 sample pairs). The apparent plasma clearance was slightly higher than the apparent saliva clearance (202+/-31 mL/h/kg vs 189+/-28 mL/h/kg; p=0.001). The mean elimination half-life was found to be 2.31+/-0.46 hours for plasma and 2.30+/-0.36 hours for saliva; these were not significantly different (p=0.83). CONCLUSION: The present study demonstrated that busulfan analysis in saliva could be a valuable and reliable alternative to plasma analysis.

Adolescent↗
PubMed1991

Lymphoid reconstitution after transplantation of congenic hematopoietic cells in busulfan-treated mice.

The effects of pretransplant conditioning with high-dose busulfan, a myeloablative but nonimmunosuppressive alkylating agent, on reconstitution of lymphoid tissues by donor cells after bone marrow transplantation (BMT) has not been extensively examined. We used flow cytometric analyses to study the kinetics and extent of lymphocyte repopulation in C57BL/6 mice (immunophenotype Ly-5.2) given graded doses of busulfan (10 to 100 mg/kg) or total body irradiation (TBI; 900 rad) and hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) from congenic Ly-5.1 donors. Mice transplanted after 10 mg/kg of busulfan had slow and incomplete lymphoid engraftment; only 6% to 11% of lymphocytes in the peripheral blood, lymph nodes, and spleen were positive for Ly-5.1 at 30 days after transplant, slightly increased to 13% to 20% at 60 days, and stabilized at 40% to 46% by 180 days after HCT. Higher doses of busulfan (20 to 100 mg/kg) provided dose-dependent congenic lymphoid reconstitution. Thirty days after HCT, the range of Ly-5.1 cells in blood, lymph nodes, and spleen of Ly-5.2 recipient mice was 43% to 54% after 20 mg/kg of busulfan, 66% to 71% after 50 to 80 mg/kg, and 77% to 85% after 100 mg/kg. Sixty days after transplant, lymphoid chimerism increased to 57% to 68% in 20 mg/kg recipients, 72% to 79% after 35 mg/kg, and 75% to 90% in animals given 50 mg/kg or greater, as seen in radiation chimeras. Despite slower early reconstitution after lower doses of busulfan, donor lymphocytes exceeded 90% to 95% by 90 to 120 days after HCT in all mice given at least 20 mg/kg. Even though busulfan lacks directly immunosuppressive properties, virtually complete sustained lymphoid reconstitution by transplanted congenic donor stem cells occurs after its administration. These observations suggest that pretreatment with busulfan may be effective in gene therapy strategies that involve infusion of autologous marrow cells into which functional genes have been inserted.

Animals↗
PubMed1981

Induction of lymphomas in mice by busulfan and chloramphenicol.

Busulfan causes long-lasting defects in the hematopoietic stem cells and in the immune system of mice. We designed studies to determine whether chloramphenicol further damaged the already defective hematopoietic stem cells of mice that were pretreated with busulfan, and we unexpectedly observed that mice given injections of the combination of busulfan and chloramphenicol developed lymphomas in relatively high incidence. The disease is invariably associated with splenomegaly and enlargement of the thymus. Leukocytosis with lymphoblasts in the peripheral blood occurred in some affected mice. The malignant cell is a lymphoblast of thymic origin. Thirteen of 37 mice which received both busulfan and chloramphenicol developed lymphomas. An additional five of the remaining 24 mice without proven lymphoma died and were not autopsied. Twelve of the 13 proven lymphomas developed within 280 days from the start of the experiment. Four of the 35 mice treated with busulfan alone developed lymphomas, and an additional five of the remaining 31 died but were not autopsied. Two of 41 mice treated with only chloramphenicol developed lymphomas. Of the mice treated with either busulfan or chloramphenicol alone that developed lymphomas, all did so more than 280 days from the start of the experiment. None of the control mice developed lymphoma. We conclude that both busulfan and chloramphenicol may induced lymphomas in mice that are not known to develop them spontaneously. The combination of both busulfan and chloramphenicol increased the frequency and accelerated the onset of the disease.

Animals↗
PubMed1998

Comparison of human liver and small intestinal glutathione S-transferase-catalyzed busulfan conjugation in vitro.

The apparent oral clearance of busulfan has been observed to vary as much as 10-fold in the population of children and adults receiving high-dose busulfan. The only identified elimination pathway for busulfan involves glutathione conjugation. The reaction is predominantly catalyzed by glutathione S-transferase (GST) A1-1, which is present in both liver and intestine. The purpose of this study was to compare busulfan Vmax/Km in cytosol prepared from adult human liver and small intestine. Tetrahydrothiophenium ion formation rate per milligram of cytosolic protein was constant along the length (assessed in 30-cm segments) of three individual small intestines. A 30-cm-long intestinal segment 90-180 cm from the pylorus was chosen to be representative of intestinal cytosolic busulfan conjugating activity. Busulfan Vmax/Km (mean +/- SD) in cytosol prepared from 23 livers and 12 small intestines was 0.166 +/- 0.066 and 0.176 +/- 0.085 microl/min/mg cytosolic protein, respectively, in incubations with 5 microM busulfan, 1 mM glutathione, and 2 mg of cytosolic protein. The relative content of GSTalpha (A1-1, A1-2, and A2-2) was compared for human liver and intestinal cytosol using Western blot. The levels of GSTalpha in liver and intestinal cytosol were 1.12 +/- 0.56 and 1.36 +/- 0.32 integrated optimal density units/5 microg cytosolic protein, respectively. Busulfan conjugation in vitro was comparable per milligram of cytosolic protein in liver and intestinal cytosol.

Busulfan↗
PubMed2005

Development of a rapid and specific assay for detection of busulfan in human plasma by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

A sensitive and specific assay for detection of busulfan in human plasma was developed. The assay is based on rapid isolation of busulfan by liquid-liquid extraction with ethyl acetate, and detection by high-performance liquid chromatography with electrospray ionization and tandem mass spectrometry. 1,6-Bis(methanesulfonyloxy)hexane, a synthesized analogue of busulfan, was used as the internal standard (IS). The acquisition was performed in the multiple reaction monitoring mode; busulfan and the IS were detected with no interferences from plasma matrix. The method was linear over the range 5-2500 ng mL(-1), with r2 > 0.99 and a run time of only 3.5 min. The intra- and inter-assay precisions were in the ranges 2.1-11.9% and 3.2-10.1%, respectively, and the intra- and inter-assay accuracies were 92.2-107.6% and 94.7-104.1%, respectively. The absolute recoveries were 82.0% (20 ng mL(-1)), 90.6% (1000 ng mL(-1)) and 80.0% (2000 ng mL(-1)) for busulfan, and 89.1% for the IS (1000 ng mL(-1)). The limits of detection and quantification were 2 and 5 ng mL(-1), respectively. The validated method was successfully applied to analyze plasma samples obtained from six adults receiving doses of 1 mg kg(-1) in a conditioning regimen prior to bone marrow transplantation. A marked intra-patient variation in busulfan concentrations during the steady state was observed, which limits the application of pharmacokinetic modeling and suggests that continuous therapeutic monitoring is necessary for adequate individualized dosing. In this regard, the present assay brings important advantages relative to other methods described in the literature, i.e., it is highly specific and simple to perform, with a rapid chromatographic run time (3.5 min), and the whole procedure can be completed in 4-5 h, which would permit dose corrections after the third dose allowing earlier and better dosing adjustments towards the target level of busulfan.

Alkylating Agents↗
PubMed1980

Response of early chick embryos to busulfan.

Busulfan, suspended in peanut oil, was injected into the yolk sac of white Leghorn chick embryos in dosages of 0.1 mg, 0.5 mg, or 1.0 mg. Embryos received a single injection of busulfan either prior to incubation, at 24, 48, 72, or 96 hours of incubation. Surviving embryos were sacrificed when they reached five days of incubation. Some embryos exposed to busulfan at 96 hours were allowed to develop to nine days of incubation to determine whether the time of initial exposure or the length of exposure to busulfan was more critical. The embryo required 48 hours to manifest the deleterious effects of busulfan. Abnormalities such as defects in the formation of the limb buds and cephalic hematomas were commonly seen in survivors no matter when exposed to busulfan. Some embryos injected at 96 hours and allowed to develop to nine days displayed edema of the body cavities. The role of busulfan in eliciting these malformations is discussed.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Pharmacokinetic and metabolic studies of busulfan in rat plasma and brain.

Busulfan kinetics were studied in the rat plasma and brain after an I.P. dose of 14C-busulfan or busulfan (15 mg/kg). The distribution of busulfan to the brain was rapid and the ratio brain/plasma concentration was 0.74 during the time-course of busulfan. The elimination half-lives in plasma and brain were 3h for intact busulfan and 8h for the 14C-radioactivity. The radioactivity remaining in plasma and brain after 24h was mostly busulfan metabolites e.g. sulfolane, 3-hydroxysulfolane and tetrahydrothiophene-1-oxide as identified by gas chromatography-mass spectrometry. The protein binding to rat plasma was low (9.2 +/- 4.4%).

Animals↗
PubMed1986

Toxicological review of busulfan (Myleran).

Busulfan is a bifunctional alkylating agent that appears to be cytotoxic to slowly proliferating or non-proliferating stem cell compartments, although its specific molecular and cellular mechanisms are unknown. It is the drug of preference in treatment of chronic myelogenous or granulocytic leukemia because its cytotoxic activity results in primary damage or destruction of hematopoietic cells. Additional effects resulting from the cytotoxicity of busulfan in hematological and other tissues, as documented by both human and animal model studies, include lethality, sterility, teratogenicity, and alteration of immune function. Busulfan has been shown to be mutagenic to microorganisms, mammalian cells in culture, Drosophila, and rodents. This agent is also considered potentially carcinogenic to humans. Various tissue hyperplasia and preneoplastic cells have been observed in animal model studies with busulfan, and case reports on human patients implicate busulfan as the causative agent in induction of secondary malignancies. Reports from human and animal studies of busulfan's cytotoxicity, teratogenicity, carcinogenicity, and mutagenicity have been reviewed. This information may be useful in a quantitative assessment of the effects of this agent and the identification of significant deficiencies in the data base. Demonstration that busulfan induces mutations in both somatic and germ cells suggests the need to assess its risk to humans.

Animals↗
PubMed2004

Improved assay for determination of busulfan by liquid chromatography using postcolumn photolysis.

A highly sensitive and time-reduced HPLC assay for the quantitative analysis of busulfan in plasma and aqueous samples is described. The assay is based on a precolumn derivatization of busulfan to 1,4-diiodobutane and UV-detection of iodide ions generated by a postcolumn photochemical dissociation of the derivative. The extraction and derivatization were carried out in a one-pot reaction without any solid phase extraction and is therefore suitable for high throughput analysis. Quantification was performed by using 1,5-pentanediol-bis-(methanesulfonate), a homologue of busulfan, as an internal standard. Linearity was demonstrated for concentrations from 50 to 10,000ng/ml. The limit of detection was found at 10ng/ml. Precision is indicated by an intra-day variety of 2.81% and by an inter-day variety of 6.61% for aqueous samples, 2.93 and 5.76% for plasma samples, respectively. The recovery of busulfan in plasma was more than 95%. No coelution with metabolites of busulfan or other drugs used in cancer therapy was found. The method was generated for measurements of busulfan in aqueous or plasma samples and applied in therapeutic drug monitoring of busulfan.

Busulfan↗
PubMed1997

Validation of a high-performance liquid chromatographic assay method for pharmacokinetic evaluation of busulfan.

The development and validation of a high-performance liquid chromatographic (HPLC) assay for determination of busulfan concentrations in human plasma for pharmacokinetic studies is described. Plasma samples containing busulfan and 1,6-bis(methanesulfonyloxy)hexane, and internal standard, were prepared by derivatization with sodium diethyldithiocarbamate (DDTC) followed by addition of methanol and extraction with ethyl acetate. The extract was dried under nitrogen and the samples reconstituted with 100 microl of methanol prior to HPLC determination. Chromatography was accomplished using a Waters NovaPak octadecylsilyl (ODS) (150 x 3.9 mm I.D.) analytical column, NovaPak ODS guard column, and mobile phase of methanol-water (80:20, v/v) at a flow-rate of 0.8 ml/min with UV detection at 251 nm. The limit of detection was 0.0200 microg/ml (signal-to-noise ratio of 6) with a limit of quantitation (LOQ) of 0.0600 microg/ml for busulfan in plasma. Calibration curves were linear from 0.0600 to 3.00 microg/ml in plasma (500 microl) using a 1/y weighting scheme. Precision of the assay, as represented by C.V. of the observed peak area ratio values, ranged from 4.41 to 13.5% (13.5% at LOQ). No day-to-day variability was observed in predicted concentration values and the bias was low for all concentrations evaluated (bias: 0 to 4.76%; LOQ: 2.91%). The mean derivatization and extraction yield observed for busulfan in plasma at 0.200, 1.20 and 2.00 microg/ml was 98.5% (range 93.4 to 107%). Plasma samples containing potential busulfan metabolites and co-administered drugs, which may be present in clinical samples, provided no response indicating this assay procedure is selective for busulfan. This method was used to analyze plasma concentrations following administration of a 1 mg/kg oral busulfan dose.

Busulfan↗
PubMed1998

Quantification of busulfan in plasma by gas chromatography-mass spectrometry following derivatization with tetrafluorothiophenol.

A specific and highly sensitive method has been developed for the determination of busulfan in plasma by gas chromatography-mass spectrometry using a deuterium-labeled busulfan (busulfan-d8) as internal standard. Plasma containing busulfan and busulfan-d8 were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to the monitoring of specific ions. The limit of quantification of the assay was 20 ng/ml and the calibration curve was linear over the range of 10 to 2000 ng/ml of derivatized busulfan. This method was in good agreement with the GC-MS assay using derivatization with sodium iodide and measuring diiodobutane. In addition, a pharmacokinetic study of busulfan was conducted in six children. The apparent oral clearance was 5.7+/-1.9 ml/kg/min and the volume of distribution was 1.0+/-0.4 l/kg and were similar to those previously reported in pediatric patients.

Alkylating Agents↗
PubMed1993

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 allogenic (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 chromatographic 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.

Administration, Oral↗