Busulfan monitoring

Busulfan has been used as part conditioning regimens in haematopoietic stem cell transplantation (HSCT) since the 1950s.^r Busulfan has a narrow therapeutic index and exhibits large pharmacokinetic (PK) variation. It is currently available in both oral and intravenous formulations. The use of oral busulfan is limited due to inter-patient and intra-patient variability in exposure, need for frequent dosing and increased first-pass metabolism, which subsequently increases the risk of toxicities such as sinusoidal obstruction syndrome (SOS) and gastrointestinal mucositis if patients are over-exposed to the drug.^r Furthermore, underexposure is also associated with adverse outcomes such as increased risk of relapse or graft rejection.^rrr

Studies using intravenous busulfan have demonstrated more predictable busulfan PK and more consistent total busulfan exposure than previously observed with the oral form.^rr It can be administered either as a once daily fixed dose, or as a daily pharmacokinetically-guided dose. The target AUC varies across the literature according to the dose and the conditioning regimen being used. It is generally set by the transplant team for patients on a case-by-case basis. In adults, pharmacokinetically-adjusted dosing to target an average daily area under the curve (AUC) of 13.1 - 24.6 mg/L.h (3200-6000 µM.min) for a 3.2 mg/kg dose has been demonstrated to limit chemotherapy-related toxicity and optimise disease outcomes in HSCT.^rr

Busulfan is primarily metabolised by the glutathione transferase enzymes, however the PK does appear to be affected by drugs metabolised by the cytochrome P450 (CYP450) systems. As a result, there is the potential for drug interactions with drugs that induce or inhibit CYP450 enzymes. The following drugs commonly used in HSCT have been known to interfere with busulfan metabolism, and therefore should be either kept to a minimum or administered throughout the entirety of busulfan treatment to ensure that targeted exposure is achieved:

• Azole antifungals such as Itraconazole, posaconazole – may reduce the metabolism of busulfan
• Iron chelating agents – may increase plasma concentrations of busulfan when administered simultaneously
• Metronidazole – may increase plasma concentrations of busulfan when infused simultaneously
• Paracetamol – may decrease the metabolism of busulfan when administered within 72 hours before commencing busulfan or when using concurrently
• Phenytoin – increased metabolism of  busulfan in the liver.

Table 1: Busulfan assay and AUC calculations in different states of Australia

	New South Wales (NSW)	Victoria (VIC)	South Australia (SA)	Tasmania (Tas)	Queensland (QLD)	Western Australia (WA)
Contact Details	Sites using CHW for busulfan assay and AUC calculations should contact Dr Christa Nath 2 weeks prior to testing. Some sites may have capacity to do their own busulfan assay and AUC calculation, therefore institutional policies and procedures should be followed. Dr. Christa Nath (email: christa.nath@health.nsw.gov.au)				Busulfan assay at Townsville Hospital is done through RBWH. Manually printed request form needs to be sent with the sample. Contact BMT quality officer or BMT coordinator. Notify Dr. Christa Nath 2 weeks prior to testing for AUC calculations	Clinical Associate Professor Sam Salman (email: sam.salman@health.wa.gov.au) Dr Sean O'Halloran (email: sean.ohalloran@health.wa.gov.au) Clinical Pharmacology and Toxicology Unit, QEII PathWest Laboratory Medicine, Nedlands, WA, 6009
Busulfan Assay	CHW				RBWH	PathWest Laboratory Medicine
AUC Calculation	CHW					PathWest Laboratory Medicine
Blood sample collection time points after completion of the first busulfan dose	Blood samples for pharmacokinetic analysis should be collected after the first busulfan dose at the following time points from the end of the infusion: 1. T = 0 2. T = 1 hours 3. T = 2 hours 4. T = 4 hours The first 3.2 mg/kg dose may be split in two and infused over 90 minutes on day 1 and day 2. This allows PK analysis and reporting of results to occur between 3-4 pm on day 2 ( using PK samples taken post day 1 infusion), which is used to predict full dose AUC. Any dose modification required to ensure levels are within the target range can therefore occur on day 3 Record the exact start and finish time of busulfan infusion and the exact time of the PK blood collections on the blood sampling form. All bloods samples need to be taken from the opposite lumen that was used to deliver the busulfan. For further details, please see Appendix 1 Combined Busulfan Sample Worksheet and Request Form from ACI Blood and Marrow Transplant & Cellular Therapies Network document TX-BMT-S65 v1 Busulfan IV PK Monitoring.					1. T = 0 hours 2. T = 15 minutes 3. T = 4 hours 4. T = 5 hours 5. T = 6 hours 6. T = 8 hours The proposed date for sampling needs to be communicated to the laboratory in advance To facilitate laboratory logistics and timely dose adjustments the first busulfan dose is given at 0200 am over 3 hours The AUC is communicated to the clinical team before the end of day 1, to enable prescription of the subsequent doses (days 2 - 4)
	Dose adjustment The necessity for dose adjustments should be determined by the clinical team. The target busulfan area under the plasma concentration vs time curve (AUC) should be clearly documented. Dose adjustments will be based on a standard formula as follows: Adjusted IV busulfan dose (mg) = actual dose (mg) x target AUC (mg/L.h) ÷ actual AUC (mg/L.h) Adjustments will be made to achieve the target AUC level. This calculation may be performed by the pharmacokinetic laboratory on request or by the clinical team. Once the dose has been calculated, it is important to maintain infusion rate of 3.2 mg/kg over 3 hours i.e. if new dose is 2.5 mg/kg then the infusion time is 140 minutes.

 CHW = The Children's Hospital Westmead, RBWH = Royal Brisbane and Women's Hospital, AUC = Area Under the Curve, T = Time, PK = Pharmacokinetic, ACI = Agency of Clinical Innovation

Busulfan plasma concentration measurement and pharmacokinetic assessment is available in the Department of Biochemistry at The Children's Hospital at Westmead (CHW). Please note:

• ​Testing can also be performed for patients being treated at other hospitals around Australia.
• The service is not available on weekends or public holidays.
• Please notify Dr Christa Nath (email: christa.nath@health.nsw.gov.au) of the proposed date for sampling at least 2 weeks prior to testing.  
• CHW target AUC reference range in adults is 13.1 – 20.5 mg/L.h (3200 – 5000 μM.min) for a 3.2 mg/kg dose. This corresponds to a range of 3.3 – 5.1 mg/L.h (800 – 1250 µM.min) for a 0.8 mg/kg dose given four times daily. The acceptable AUC 0–∞ varies according to the dose, the conditioning regimen and the protocol used. Correct interpretation and clinical usage of the predicted dose ultimately rests with the clinical team taking into account demographic, medication related and clinical variables.
• Busulfan is unstable in blood at room temperature, so samples must be sent to the laboratory for centrifugation to separate the plasma immediately after blood collection. Plasma should be immediately stored in a -40^oC freezer. If a delay is expected samples should be stored on ice or in a fridge until it can be separated and the plasma stored at -40^oC or lower. Failure to follow these instructions can result in overdosing the patient based on an underestimation of patient exposure to busulfan and increasing the dose unnecessarily. Refer to institution policy regarding the transport of blood samples
• For further details, please see Appendix 1 Combined Busulfan Sample Worksheet and Request Form from Agency of Clinical Innovation Blood and Marrow Transplant & Cellular Therapies Network document TX-BMT-S65 v1 Busulfan IV PK Monitoring.

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Bibliography

Bubalo, J., P.A. Carpenter, N. Majhail et al. 2014. "Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee". Biol Blood Marrow Transplant. 20(5):600-616.

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Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the current published literature on the dosing of pharmacologic agents used for HCT preparative regimens with specific focus on the obese patient population. The review found that dose adjustments for obesity have, to date, been based empirically or extrapolated from published data in the nontransplantation patient population. As a result, the Committee determined that clear standards or dosing guidelines are unable to be made for the obese population because Level I and II evidence are unavailable at this time. Instead, the Committee provides a current published literature review to serve as a platform for conditioning agent dose selection in the setting of obesity. A necessary goal should be to encourage future prospective trials in this patient population because further information is needed to enhance our knowledge of the pharmacokinetics and pharmacodynamics of conditioning agents in the setting of obesity.

Nath, C.E, J.W. Earl, N. Pati et al. 2008. "Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients." Br J Clin Pharmacol. 66(1):50-59.

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Aim: To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease. Methods: Busulphan (120 mg m(-2), 130 mg m(-2) or 3.2 mg kg(-1)) was administered over median 2.1 h. Blood samples (4-10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration-time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m(-2) dose in 13 children who had busulphan pharmacokinetic monitoring. Results: Clearance of i.v. busulphan in 40 children was 4.78 +/- 2.93 l h(-1) (% CV 61%), 0.23 +/- 0.08 l h(-1) kg(-1) (% CV 35%) and 5.79 +/- 1.59 l h(-1) m(-2) (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h(-1)) and CL (l h(-1) kg(-1)), but not with CL (l h(-1) m(-2)). AUC normalized to the 130 mg m(-2) dose ranged from 14.1 to 56.3 mg l(-1) x h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h(-1) m(-2)) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children. Conclusions: There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h(-1) m(-2)) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.

Version 6

Date

Summary of changes

21/08/2024

Iron-chelating agents added to list of drugs known to affect busulfan exposure. Appendix 1 Combined Busulfan Sample Worksheet and Request Form from ACI Blood and Marrow Transplant & Cellular Therapies Network document TX-BMT-S65 v1 Busulfan IV PK Monitoring replaces TCHW busulfan request form and TCHW busulfan PK minimum blood sampling form; therapeutic dose monitoring blood sample time points aligned with new form. Increase to version 6.

Version 5

Date

Summary of changes

02/05/2023

Document reviewed out of session by the BMT reference committee. The following updates made to the document: Information gathered from all the states in Australia and incorporated into a table  Contact details for WA and NSW updated Updated TCHW busulfan sampling form and busulfan request form Busulfan plasma exposure unit updated to include AUC in harmonised units of mg/L.h as per 2019 consensus statement by McCune et al. TCHW busulfan AUC reference range included in the table Version change to V.5.

Version 4

Date	Summary of changes
31/07/2020	Document reviewed and presented at the 2020 BMT reference committee meeting. Discussion continued via email and the following changes were made prior to publication:  Updated state guidelines updated busulfan sampling and busulfan request forms Version change to V.4.

Version 3

Date	Summary of changes
31/05/2017	Transferred to new eviQ website. Version number change to V.2. ACI ID 229 old site.
22/09/2017	Document reviewed and presented at the September BMT reference committee meeting. Discussion continued via email and the following changes were made prior to publication:  removed sentence: "it is the consensus of the eviQ BMT Reference Committee not to split the first dose of busulfan"  updated busulfan sampling and busulfan request forms Version change to V.3.