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The pharmacokinetics and pharmacodynamics of busulfan when combined with melphalan as conditioning in adult autologous stem cell transplant recipients.
Ann Hematol. 2018 Dec; 97(12):2509-2518.AH

Abstract

Busulfan (Bu) is an alkylating agent widely used in conditioning regimes prior to stem cell transplantation (SCT), most commonly in combination with cyclophosphamide (Bu-cy) or fludarabine (Bu-flu) as myeloablative conditioning prior to allograft or with high-dose melphalan (Bu-mel) prior to autologous SCT. Despite many decades of Bu use, initially orally but now intravenously (IV), a paucity of pharmacokinetic (PK) and pharmacodynamic (PD) data exists to inform evidence-based guidelines as how best to balance the efficacy and toxicity of this agent. This is a non-randomized retrospective real-world study at three hospitals investigating the role of PK guidance in dosing Bu in the setting of IV Bu-mel autologous SCT. The primary intent was to examine how effectively PK assessment could be used to achieve a desirable drug exposure and to evaluate factors, particularly, age, sex, actual weight, body mass index (BMI), body surface area (BSA), disease, number of prior treatments, renal function, and the use of concomitant medications that may influence Bu exposure. All patients underwent PK analysis on a test dose of Bu (1.6 mg/kg, i.e., 50% of the first dose) on D-7 and subsequently received a second 1.6 mg/kg dose on D-6. Bu dose was calculated using actual body weight (ABW) if patients were less than ideal body weight (IBW), or adjusted ideal body weight (AIBW) if ABW was greater than IBW. Thereafter, at the discretion of the investigator, the group was divided into two; a weight-based cohort at two hospitals and a PK-guided cohort at the third hospital. Thirty-seven patients received PK-adjusted dosing guided by the results of the initial PK results, targeting a specific Bu exposure expressed as the area-under-the-concentration-versus-time curve (AUC) of between 4000 and 5000 μmol min/day (median 4800). The remaining 27 patients received unadjusted weight-based doses with a further three doses of 3.2 mg/kg of Bu infused over 180 min (D-5 to - 3) irrespective of their initial PK results. For the purposes of the analysis, we selected a target AUC of 4800 μmol min/day in this group, equivalent to the median targeted AUC in the PK-adjusted group. All patients subsequently had repeated PK analysis on D-5 after receiving their "therapeutic" Bu dose. Mel (140 mg/m[2] or 100 mg/m[2]) IV was given on D-2. Sixty-four adult patients were enrolled. Patients who received PK-guided Bu dosing received a higher median Bu dose than the unadjusted weight-based cohort (3.5 mg/kg vs 3.2 mg/kg respectively, p = 0.007). Eighty-one percent (30/37) of patients in the PK-guided group achieved their target AUC (± 15%) compared with 56% (15/27) in the weight-based cohort (p = 0.027). The respective median AUCs of 5064 μmol min/day (range 3639-6157 μmol min/day) and 4854 μmol min/day (range 3251-6305 μmol min/day) were not significantly different (p = 0.16). Multivariate analysis identified ABW as the only independent variable that affected the relationship between Bu dosing and exposure (p = 0.02) with heavier patients achieving lower than anticipated AUCs for the dose they received. On D-5, within the weight-based cohort, the mean AUCs were 12% higher than anticipated based on initial D-7 PK. No correlation between AUC and grade 3-4 transplant-related toxicities were observed, although only three patients had AUCs > 6000 μmol min/day. These results suggest that PK-directed Bu dosing may be of benefit in achieving a target level of drug exposure, with larger studies needed to determine the clinical significance of this strategy.

Authors+Show Affiliations

Department of Clinical Haematology, Austin Hospital, Melbourne, Australia. abbey.willcox@monash.edu. Australian Centre for Blood Diseases, Monash University, Melbourne, Australia. abbey.willcox@monash.edu.Department of Clinical Haematology and Bone Marrow Transplant, The Royal Melbourne Hospital, Melbourne, Australia.The Children's Hospital at Westmead, Sydney, Australia.Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.Department of Clinical Haematology, Austin Hospital, Melbourne, Australia.Department of Clinical Haematology and Bone Marrow Transplant, The Royal Melbourne Hospital, Melbourne, Australia.The Children's Hospital at Westmead, Sydney, Australia.Department of Clinical Haematology and Bone Marrow Transplant, The Royal Melbourne Hospital, Melbourne, Australia.Department of Clinical Haematology, Austin Hospital, Melbourne, Australia.

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study

Language

eng

PubMed ID

30051172

Citation

Willcox, Abbey, et al. "The Pharmacokinetics and Pharmacodynamics of Busulfan when Combined With Melphalan as Conditioning in Adult Autologous Stem Cell Transplant Recipients." Annals of Hematology, vol. 97, no. 12, 2018, pp. 2509-2518.
Willcox A, Wong E, Nath C, et al. The pharmacokinetics and pharmacodynamics of busulfan when combined with melphalan as conditioning in adult autologous stem cell transplant recipients. Ann Hematol. 2018;97(12):2509-2518.
Willcox, A., Wong, E., Nath, C., Janson, B., Harrison, S. J., Hoyt, R., Bajel, A., Shaw, P., Ritchie, D., & Grigg, A. (2018). The pharmacokinetics and pharmacodynamics of busulfan when combined with melphalan as conditioning in adult autologous stem cell transplant recipients. Annals of Hematology, 97(12), 2509-2518. https://doi.org/10.1007/s00277-018-3447-x
Willcox A, et al. The Pharmacokinetics and Pharmacodynamics of Busulfan when Combined With Melphalan as Conditioning in Adult Autologous Stem Cell Transplant Recipients. Ann Hematol. 2018;97(12):2509-2518. PubMed PMID: 30051172.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The pharmacokinetics and pharmacodynamics of busulfan when combined with melphalan as conditioning in adult autologous stem cell transplant recipients. AU - Willcox,Abbey, AU - Wong,Eric, AU - Nath,Christa, AU - Janson,Brett, AU - Harrison,Simon J, AU - Hoyt,Rosemary, AU - Bajel,Ashish, AU - Shaw,Peter, AU - Ritchie,David, AU - Grigg,Andrew, Y1 - 2018/07/26/ PY - 2018/01/21/received PY - 2018/07/17/accepted PY - 2018/7/28/pubmed PY - 2018/11/6/medline PY - 2018/7/28/entrez KW - Autologous stem cell transplant KW - Busulfan KW - Busulphan KW - Melphalan KW - Pharmacokinetics, pharmacodynamics SP - 2509 EP - 2518 JF - Annals of hematology JO - Ann Hematol VL - 97 IS - 12 N2 - Busulfan (Bu) is an alkylating agent widely used in conditioning regimes prior to stem cell transplantation (SCT), most commonly in combination with cyclophosphamide (Bu-cy) or fludarabine (Bu-flu) as myeloablative conditioning prior to allograft or with high-dose melphalan (Bu-mel) prior to autologous SCT. Despite many decades of Bu use, initially orally but now intravenously (IV), a paucity of pharmacokinetic (PK) and pharmacodynamic (PD) data exists to inform evidence-based guidelines as how best to balance the efficacy and toxicity of this agent. This is a non-randomized retrospective real-world study at three hospitals investigating the role of PK guidance in dosing Bu in the setting of IV Bu-mel autologous SCT. The primary intent was to examine how effectively PK assessment could be used to achieve a desirable drug exposure and to evaluate factors, particularly, age, sex, actual weight, body mass index (BMI), body surface area (BSA), disease, number of prior treatments, renal function, and the use of concomitant medications that may influence Bu exposure. All patients underwent PK analysis on a test dose of Bu (1.6 mg/kg, i.e., 50% of the first dose) on D-7 and subsequently received a second 1.6 mg/kg dose on D-6. Bu dose was calculated using actual body weight (ABW) if patients were less than ideal body weight (IBW), or adjusted ideal body weight (AIBW) if ABW was greater than IBW. Thereafter, at the discretion of the investigator, the group was divided into two; a weight-based cohort at two hospitals and a PK-guided cohort at the third hospital. Thirty-seven patients received PK-adjusted dosing guided by the results of the initial PK results, targeting a specific Bu exposure expressed as the area-under-the-concentration-versus-time curve (AUC) of between 4000 and 5000 μmol min/day (median 4800). The remaining 27 patients received unadjusted weight-based doses with a further three doses of 3.2 mg/kg of Bu infused over 180 min (D-5 to - 3) irrespective of their initial PK results. For the purposes of the analysis, we selected a target AUC of 4800 μmol min/day in this group, equivalent to the median targeted AUC in the PK-adjusted group. All patients subsequently had repeated PK analysis on D-5 after receiving their "therapeutic" Bu dose. Mel (140 mg/m[2] or 100 mg/m[2]) IV was given on D-2. Sixty-four adult patients were enrolled. Patients who received PK-guided Bu dosing received a higher median Bu dose than the unadjusted weight-based cohort (3.5 mg/kg vs 3.2 mg/kg respectively, p = 0.007). Eighty-one percent (30/37) of patients in the PK-guided group achieved their target AUC (± 15%) compared with 56% (15/27) in the weight-based cohort (p = 0.027). The respective median AUCs of 5064 μmol min/day (range 3639-6157 μmol min/day) and 4854 μmol min/day (range 3251-6305 μmol min/day) were not significantly different (p = 0.16). Multivariate analysis identified ABW as the only independent variable that affected the relationship between Bu dosing and exposure (p = 0.02) with heavier patients achieving lower than anticipated AUCs for the dose they received. On D-5, within the weight-based cohort, the mean AUCs were 12% higher than anticipated based on initial D-7 PK. No correlation between AUC and grade 3-4 transplant-related toxicities were observed, although only three patients had AUCs > 6000 μmol min/day. These results suggest that PK-directed Bu dosing may be of benefit in achieving a target level of drug exposure, with larger studies needed to determine the clinical significance of this strategy. SN - 1432-0584 UR - https://www.unboundmedicine.com/medline/citation/30051172/The_pharmacokinetics_and_pharmacodynamics_of_busulfan_when_combined_with_melphalan_as_conditioning_in_adult_autologous_stem_cell_transplant_recipients_ DB - PRIME DP - Unbound Medicine ER -