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The Annals of Pharmacotherapy Sep 1994To review the current published studies evaluating the pharmacokinetics, clinical efficacy, safety, and toxicity of busulfan in pediatric and adult patients. (Comparative Study)
Comparative Study Review
OBJECTIVE
To review the current published studies evaluating the pharmacokinetics, clinical efficacy, safety, and toxicity of busulfan in pediatric and adult patients.
DATA SOURCES
English-language literature published between 1953 and 1993 was analyzed; pertinent literature was reviewed.
STUDY SELECTION
Emphasis was placed on pharmacologic studies and clinical trials involving busulfan therapy both in myeloproliferative disorders and in conditioning regimens for autologous or allogeneic bone marrow transplantation.
DATA EXTRACTION
Data from both pediatric and adult studies were evaluated; emphasis was placed on the relationship between plasma concentrations of busulfan and its efficacy and toxicity.
DATA SYNTHESIS
Busulfan has been used widely at conventional dosages (1-12 mg/d) for the treatment of patients with chronic myelogenous leukemia (CML). Busulfan at high doses (usually 16 mg/kg) given with other cytotoxic drugs (especially cyclophosphamide) is a common preparative regimen in patients undergoing allogeneic or autologous bone marrow transplantation (BMT) for acute or chronic leukemia and other nonmalignant disorders (e.g., hemoglobinopathies, inborn error of immune system, congenital metabolic disorders). Pharmacokinetics of high-dose busulfan are age-dependent. Busulfan systemic exposure and, thus, tissue and tumor exposure are lower in children than with adults. Relationships between toxicity (principally neutropenia, hepatic veno-occlusive disease, incidence of seizures) and drug exposure were found for busulfan.
CONCLUSIONS
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.
Topics: Age Factors; Blood Proteins; Bone Marrow Transplantation; Busulfan; Humans; Models, Biological; Myeloproliferative Disorders; Protein Binding; Reproducibility of Results
PubMed: 7803883
DOI: 10.1177/106002809402800911 -
Journal of Pediatric Oncology Nursing :... Jul 1996
Review
Topics: Bone Marrow Transplantation; Busulfan; Chemistry, Pharmaceutical; Drug Interactions; Drug Storage; Humans; Immunosuppressive Agents
PubMed: 8755444
DOI: 10.1177/104345429601300308 -
Expert Opinion on Drug Metabolism &... Aug 2009This paper focuses primarily on the data published in the last decade about the pharmacokinetics and pharmacodynamics of oral and intravenous (i.v.) busulfan,... (Review)
Review
This paper focuses primarily on the data published in the last decade about the pharmacokinetics and pharmacodynamics of oral and intravenous (i.v.) busulfan, therapeutic drug monitoring and clinical outcome in hematopoietic stem cell transplant (HCT) patients. Busulfan is commonly used in HCT as it is toxic to the marrow. Busulfan is available as oral or i.v. formulation. The most common significant toxicity of busulfan is sinusoidal obstruction syndrome. Even with the introduction of i.v. busulfan, variability in the systemic concentrations of busulfan after weight-based dosing and the association between busulfan plasma exposure and outcome in HCT patients have led to the continued use of therapeutic drug monitoring of busulfan. New strategies for personalizing busulfan dosing are being studied to maximize the use of busulfan for optimal disease control with the least toxicity to HCT patients. One such strategy currently being evaluated is if busulfan clearance can be accurately predicted by genetic polymorphism of glutathione S-transferase (GST), with the currently available data suggesting that GST polymorphisms cannot be used to personalize busulfan dosing.
Topics: Adult; Busulfan; Child; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Pharmacogenetics
PubMed: 19611402
DOI: 10.1517/17425250903107764 -
Clinical Pharmacokinetics Jan 2021We aimed to review the pharmacokinetics (PK) of intravenous busulfan in paediatric patients, identify covariate factors influencing exposure, investigate evidence of... (Review)
Review
We aimed to review the pharmacokinetics (PK) of intravenous busulfan in paediatric patients, identify covariate factors influencing exposure, investigate evidence of changes in PK behaviour over time, and correlate exposure with efficacy and toxicity outcomes. A literature review was undertaken of original research published between 2007 and 2019, investigating the PK and pharmacodynamics (PD) of intravenous busulfan in patients ≤ 18 years of age. The review identified 41 publications characterising the PK, and 45 publications describing the PD, of busulfan. Median typical clearance (CL) was 0.22 L/h/kg and median typical volume of distribution was 0.69 L/kg. Patient weight, age, glutathione-S-transferase A1 (GSTA1) genotype and busulfan dosing day/time were the most commonly identified factors affecting CL. Of nine studies investigating changes in CL, seven reported reduced CL over the 4-day course of treatment. Exposure monitoring methods and therapeutic targets were heterogeneous across studies. Relationships between busulfan exposure and patient outcomes were observed in five studies. One study observed a cumulative area under the concentration-time curve over all days of treatment of between 78 and 101 mg/L·h, and two studies observed an average concentration at first dose of < 600 ng/mL improved overall survival, transplant-related mortality, or relapse. One study observed increased sinusoidal obstructive syndrome with maximum busulfan concentration > 1.88 ng/mL. Patient weight, age and GSTA1 genotype are important covariates to consider when individualising busulfan therapy. Reduced busulfan CL over time may need to be accounted for, particularly in patients not receiving phenytoin co-therapy. Standardised monitoring of busulfan exposure over the entire course of treatment and further investigation of the role of busulfan metabolites and pharmacogenomics is warranted.
Topics: Administration, Intravenous; Body Weight; Busulfan; Child; Genotype; Hematopoietic Stem Cell Transplantation; Humans
PubMed: 33128207
DOI: 10.1007/s40262-020-00947-2 -
Current Drug Safety Jan 2008Busulphan (1, 4-bis [methanesulfonyl-y] butane) is a bi-functional alkylating agent that, in combination with cyclophosphamide, has been commonly used in conditioning... (Review)
Review
Busulphan (1, 4-bis [methanesulfonyl-y] butane) is a bi-functional alkylating agent that, in combination with cyclophosphamide, has been commonly used in conditioning regimens before hematological stem cell transplantation (HSCT) for nearly 20 years. Busulfan has a very narrow therapeutic index, and acute toxicity may be related to absorption and disposition of the drug and metabolites. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in infants and small children. An intravenous busulfan formula was approved nearly 40 years after the approval of the oral formulation. Busulfan levels expressed as the area under the concentration-time curve (AUC) higher than 1500 microM* minute were reported to increase the risk of developing veno-occlusive disease (VOD), while low levels may result in engraftment failure or disease relapse. VOD occurs in 11-40% of patients undergoing HSCT and is associated with death in 3.3% of patients. Measurement of individual plasma busulfan levels during oral or intravenous dosing to obtain an AUC is likely to provide the necessary elements to monitor the drug disposition, ensuring efficacy and preventing toxicity of patients undergoing HSCT. It is also important to consider the busulfan drug-drug interactions and adverse drug reactions that can develop during the therapeutic process. Busulfan therapeutic drug monitoring and dose-adjustment should be performed in specialized laboratories staffed by well-trained personnel.
Topics: Animals; Area Under Curve; Busulfan; Drug Interactions; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Injections, Intravenous
PubMed: 18690982
DOI: 10.2174/157488608783333899 -
Drug Discovery Today Oct 2014Busulfan- and treosulfan-based conditionings are the cornerstone of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Although both drugs are... (Review)
Review
Busulfan- and treosulfan-based conditionings are the cornerstone of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Although both drugs are alkylating agents, their mechanisms of action, pharmacokinetics (PK) and toxicity profiles are different. Experience with busulfan in pediatric HSCT is broad and the knowledge on the pharmacodynamics (PD), PK and, to a lesser extent, pharmacogenetics (PG) has resulted in a more effective therapy. Treosulfan has only recently been introduced in pediatric HSCT and is considered a promising new therapy because of its beneficial toxicity profile. However, knowledge of the PK and PG of treosulfan is limited. In this review, we describe the pharmacology of both agents and discuss factors causing variability in PK in relation to therapeutic outcome in HSCT.
Topics: Animals; Antineoplastic Agents, Alkylating; Busulfan; Child; Drug Monitoring; Hematopoietic Stem Cell Transplantation; Humans; Polymorphism, Genetic; Precision Medicine
PubMed: 24747172
DOI: 10.1016/j.drudis.2014.04.005 -
Anticancer Research 1994High-dose busulfan is used in conditioning regimens before allogeneic or autologous bone marrow transplantation (BMT) in adults and children. During the last six years,... (Review)
Review
High-dose busulfan is used in conditioning regimens before allogeneic or autologous bone marrow transplantation (BMT) in adults and children. During the last six years, several studies have established the wide inter- and intrapatient variability of high-dose busulfan disposition. Clearance rate ranges from 0.8 to 20 ml/min/kg. Some factors of variability have been identified: age, alteration in hepatic functions, disease, circadian rhythmicity, drug interactions. Using a fixed dose of busulfan, wide interpatient variability in systemic exposure is thus expected, with eventual consequences on toxicity and efficacy. In adults, a pharmacodynamic relationship between a high busulfan systemic exposure and the occurrence of hepatic veno-occlusive disease (HVOD) has been established. A prospective controlled study demonstrated that busulfan dose-adjustment decreased the morbidity and mortality of HVOD in adults. So far, pharmacodynamic studies in children have failed to establish a toxic level. The present paper analyses the rationale for busulfan dose adjustment, and focuses on the eventual pitfalls that may jeopardize its reliability (drug absorption, chronopharmacology, drug interaction within the conditioning regimen, complex pathophysiology of HVOD). Further pharmacodynamic studies are required to establish a minimum therapeutic threshold in systemic exposure for bone marrow engraftment, especially in children undergoing HLA-compatible or incompatible allogeneic BMT for non malignant disease. The definition of a therapeutic window according to the disease and the type of BMT, along with the development of iv-busulfan, will allow accurate and effective pharmacologically-guided dose adjustment of high-dose busulfan. By the end of the century, busulfan plasma level monitoring and dose adjustment at the individual level may improve the outcome of patients undergoing BMT.
Topics: Administration, Oral; Age Factors; Bone Marrow Transplantation; Busulfan; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Humans; Intestinal Absorption
PubMed: 7825973
DOI: No ID Found -
Biology of Blood and Marrow... Dec 2019It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell...
It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell transplantation (HCT). However, there are no published PK data in patients with Fanconi anemia (FA), who are known to have baseline DNA repair defect and related inherent sensitivity to chemotherapy. In our prospective, multi-institutional study of alternative donor HCT for FA using chemotherapy-only conditioning, we replaced the single dose of total-body irradiation with BU at initial doses of 0.8 to 1.0 mg/kg and 0.6 to 0.8 mg/kg given i.v. every 12 hours for 4 doses. Patients received the first dose of i.v. busulfan on day -8, and blood levels for PK were obtained. PK samples were drawn following completion of infusion. BU PK levels were collected at 2 hours, 2 hours and 15 minutes, and 4, 5, 6, and 8 hours from the start of infusion. The remaining 3 doses of BU were given on days -7 and -6. Thirty-seven patients with available BU PK data with a median age of 9.2 years (range, 4.3 to 44 years) are included in the final analyses. The overall BU PK profile in patients with FA is similar to non-FA patients after considering their body weight. In our cohort, a strong correlation between BU clearance and weight supports current practice of per kilogram dosing. However, not surprisingly, we show that the disease (ie, host) sensitivity related to FA is the main determinant of total dose of BU that can be safely administered to patients in this high-risk population. On the basis of our results, we propose an optimal BU concentration at steady-state level of ≤350 ng/mL (equivalent to total cumulative exposure of 16.4 mg*h/L for 4 doses over 2 days) for patients with FA undergoing HCT. To our knowledge, this is the first and largest report of prospective BU PK in patients with FA undergoing HCT, providing an optimal BU target cutoff to achieve stable donor engraftment while avoiding excessive toxicity.
Topics: Adolescent; Adult; Allografts; Busulfan; Child; Child, Preschool; Fanconi Anemia; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Transplantation Conditioning
PubMed: 31326610
DOI: 10.1016/j.bbmt.2019.07.014 -
Therapie 2022
Topics: Busulfan; Humans; Skin
PubMed: 35034779
DOI: 10.1016/j.therap.2021.12.019 -
Therapeutic Drug Monitoring Oct 2021Personalizing busulfan doses to target a narrow plasma exposure has improved the efficacy and lowered the toxicity of busulfan-based conditioning regimens used in...
BACKGROUND
Personalizing busulfan doses to target a narrow plasma exposure has improved the efficacy and lowered the toxicity of busulfan-based conditioning regimens used in hematopoietic cell transplant. Regional regulations guide interlaboratory proficiency testing for busulfan concentration quantification and monitoring. To date, there have been no comparisons of the busulfan pharmacokinetic modeling and dose recommendation protocols used in these laboratories. Here, in collaboration with the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring and Clinical Toxicology, a novel interlaboratory proficiency program for the quantitation in plasma, pharmacokinetic modeling, and dosing of busulfan was designed. The methods and results of the first 2 rounds of this proficiency testing are described herein.
METHODS
A novel method was developed to stabilize busulfan in N,N-dimethylacetamide, which allowed shipping of the proficiency samples without dry ice. In each round, participating laboratories reported their results for 2 proficiency samples (one low and one high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. All participants were blinded to the answers; descriptive statistics were used to evaluate their overall performance. The guidelines suggested that answers within ±15% for busulfan concentrations and ±10% for busulfan plasma exposure and dose recommendation were to be considered accurate.
RESULTS
Of the 4 proficiency samples evaluated, between 67% and 85% of the busulfan quantitation results were accurate (ie, within 85%-115% of the reference value). The majority (88% round #1; 71% round #2) of the dose recommendation answers were correct.
CONCLUSIONS
A proficiency testing program by which laboratories are alerted to inaccuracies in their quantitation, pharmacokinetic modeling, and dose recommendations for busulfan in hematopoietic cell transplant recipients was developed. These rounds of proficiency testing suggests that additional educational efforts and proficiency rounds are needed to ensure appropriate busulfan dosing.
Topics: Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Laboratory Proficiency Testing; Quality Control; Transplantation Conditioning
PubMed: 33675302
DOI: 10.1097/FTD.0000000000000862