Busulfan is used in many conditioning regimens in allogeneic haematopoietic stem cell transplantation. Here, Drs Rick Admiraal and Claudia Langebrake discuss a recent EBMT position paper they co-authored on therapeutic drug monitoring of busulfan to enhance transplant success rates and patient outcomes in Europe and provide expert guidance on implementing therapeutic drug monitoring initiatives at local centres.
Busulfan is an alkylating anti-neoplastic agent that has been used in the management of myeloproliferative disorders since the 1950s. It is now an important component of many preparative conditioning regimens for allogeneic haematopoietic stem cell transplantation, particularly in Europe.
As such, the Pharmacist Committee of the European Society for Bone Marrow Transplantation (EBMT) recently published a position paper on therapeutic drug monitoring of busulfan, offering pharmacists a practical guide to its implementation.
Busulfan pharmacokinetics overview
The pharmacokinetics of busulfan is variable and shows large inter-individual variability with an up to three-fold variability in clearance in children and adults.1
While part of this variability is explained by body weight2 and glutathione S-transferase A1 (GSTA1) activity,3 the pharmacokinetics in an individual patient is still hard to predict.
Busulfan is also partly metabolised by conjugation with glutathione, resulting in intra-individual variability in drug clearance.4 Busulfan also interacts with commonly used drugs, including paracetamol and azoles.5
Given the already substantial variability in pharmacokinetics, we strongly advise against using oral busulfan, as this greatly reduces the chance of reaching optimal exposure.
Regarding its therapeutic window, over-exposure to busulfan is associated with sinusoidal obstruction syndrome – previously known as veno-occlusive disease – and increased therapy-related mortality. Under-exposure to busulfan can lead to increased risks for relapse and graft failure.
The optimal area under the curve (AUC) is less well-defined for adults than for paediatric patients. However, most studies agree on an optimal AUC of 80–100 mg*h/L in a myeloablative setting.6,7
The evidence is less conclusive for other settings, including reduced-intensity conditioning, triple alkylator chemotherapy or haplo-identical transplant.
The importance of optimised dosing
The above underlines the importance and the need for therapeutic drug monitoring to optimise treatment outcomes.
Personalised dosing with therapeutic drug monitoring has been shown to decrease severe toxicities, graft rejection rates and relapse rates.8 Consequently, busulfan therapeutic drug monitoring is recommended by the EBMT Pharmacists Committee, especially for children, myeloablative conditioning and conditioning regimens developed with therapeutic drug monitoring.
However, according to a survey by the EBMT in 2017, few centres in Europe regularly use therapeutic drug monitoring for busulfan.9
Therapeutic drug monitoring for busulfan: a step-by-step guide
To help centres implement such a procedure, the Pharmacist Committee of the EBMT developed a position paper and stepwise guide covering aspects of busulfan therapeutic drug monitoring.10 Key points are summarised below.
- Starting dose
Therapeutic drug monitoring aims to optimise the likelihood that a patient will reach target exposure and have optimised transplant outcomes.
A 3.2 mg/kg/day starting dose is advised in non-obese adults. Obese patients – those with a body mass index >25 – should receive a dose based on adjusted ideal body weight (AIBW25), which is the sum of the ideal body weight and 25% of the excess weight over the ideal body weight.11
Currently, there is not enough evidence for a dose reduction in those with a severe decrease in hepatic function, and this is likely controlled through therapeutic drug monitoring.
The recommended starting dose for children differs substantially between publications and the Summaries of Product Characteristics (SmPCs) from the US and Europe.
Both SmPCs result in relatively low exposures, leading to expected dose increases in most patients when targeting an AUC of 90 mg*h/L. It is therefore advised to use any of the available pharmacokinetic-model-derived dosing nomograms.2,12–14 The nomograms can be found in the publications or any of the available Bayesian dose adaptation tools.15
- Administration strategy
While many centres administer busulfan every six hours (four times a day), there is no strong evidence that this leads to different outcomes compared with once-daily dosing (OD). The former dosing strategy transpired because busulfan was only available orally as 2-mg tablets before introducing the intravenous formulation, so the total dose was divided into four doses for convenience. Also, besides patient comfort, OD dosing is estimated to markedly reduce patient costs.
- Calculating AUC and sampling
The optimal time points for sampling busulfan depend greatly on the method used to calculate the AUC. While the frequent and dense sampling of eight to 10 samples is pivotal for accurate estimation of AUC using non-compartmental analyses (NCA), a limited sampling scheme with a maximum of four samples is sufficient when using model-informed precision dosing (MIPD).
There are many commercial and freely available software MIPD packages.15
MIPD has several advantages over NCA, including the necessity for fewer samples, more accurate predictions of the true AUC and the incorporation of decreasing busulfan clearance due to glutathione depletion in children.16 MIPD can be more challenging as it requires specialised software and greater pharmacological expertise than NCA.
Compared with MIPD, it has been shown that NCA leads to major under- and overpredictions in different patient populations.
The samples should be taken from another lumen or catheter to prevent contamination. After drawing, samples should be refrigerated as busulfan is unstable at room temperature.
- Assaying
Many assays are available, however, liquid chromatography coupled with mass spectrometry is most frequently used.
Some groups are investigating sampling dried blood spots as this may dramatically reduce logistical challenges, especially when the samples need to be shipped for analysis.
- Validation and monitoring
While many assays have high accuracy in measuring busulfan concentrations, validating and monitoring the reported concentrations across laboratories is paramount. There are several inter-laboratory proficiency programmes and the test scheme developed by the Dutch Foundation for Quality Assessment in Medical Laboratories is the most widely used in Europe.17
- Logistical requirements
In terms of infrastructure and finances, implementing a protocol for busulfan therapeutic drug monitoring involves acquiring an analyser, an MIPD software package and delivering training for personnel.
The price per sample depends greatly on the number of patients treated with busulfan and the use of both the software and analyser for other purposes. Centres with neither the software nor an analyser available might consider outsourcing the therapeutic drug monitoring procedure to other hospitals as an option requiring less financial investment.
Conclusion
This article provides a step-by-step overview of how to perform therapeutic drug monitoring based on the recent EBMT position paper. We urge centres to implement busulfan therapeutic drug monitoring, as it can enhance success rates of haematopoietic stem cell transplantation and patient outcomes while harmonising practices across European transplant centres.
Authors
Rick Admiraal MD PhD
Department of Stem Cell Transplantation, Princess Maxima Centre for Pediatric Oncology, Utrecht, The Netherlands
Claudia Langebrake PharmD PhD
Department of Stem Cell Transplantation and Hospital Pharmacy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
References
1 McCune JS, Holmberg LA. Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol 2009;5:957–69.
2 Bartelink IH et al. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet 2012;51:331–45.
3 Ansari M et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: A multicenter study. Oncotarget 2017;8:90852–67.
4 Langenhorst JB et al. A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance. Br J Clin Pharmacol 2020;86:1499–509.
5 Myers AL et al. Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review. Expert Opin Drug Metab Toxicol 2017; 3: 901–23.
6 Tamari R et al. Association between busulfan exposure and survival in patients undergoing a CD34+ selected stem cell transplantation. Blood Adv 2023;7:5225–33.
7 Bartelink IH et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol 2016;3:e526–e536.
8 Andersson BS et al. Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transplant 2017;52:580–7.
9 Ruutu T et al. Use of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation in adults: a survey by the Transplant Complications Working Party of the EBMT. Bone Marrow Transplant 2019;54:2013–19.
10 Domingos V et al. A practical guide to therapeutic drug monitoring in busulfan: recommendations from the Pharmacist Committee of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2024;1–13.
11 Shalhoub SD et al. Busulfan Pharmacokinetics Using 25% Adjusted Body Weight in Obese Stem Cell Transplant Patients. Biol Blood Marrow Transplant 2020;26:S386.
12 McCune JS et al. Busulfan in Infant to Adult Hematopoietic Cell Transplant Recipients: A Population Pharmacokinetic Model for Initial and Bayesian Dose Personalization. Clin Cancer Res 2014;20:754–63.
13 Nava T et al. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. Br J Clin Pharmacol 2018;84:1494–504.
14 Ben Hassine K et al. Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study. CPT Pharmacometrics Syst Pharmacol 2021;10:1043–56.
15 Kantasiripitak W et al. Software Tools for Model-Informed Precision Dosing: How Well Do They Satisfy the Needs? Front Pharmacol 2020;11:doi:10.3389/fphar.2020.00620.
16 Shukla P et al. Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population. Front Pharmacol 2020;11:1–8.
17 Kweekel DM et al. Busulfan Interlaboratory Proficiency Testing Program Revealed Worldwide Errors in Drug Quantitation and Dose Recommendations. Ther Drug Monit 2023;45(6):760–5.
