Dosing algorithm revisit for busulfan following IV infusion

Wang, Yanlin; Kato, Kazunobu; Gallo, Christopher Le; Armstrong, Elizabeth; Rock, Edwin P.

doi:10.1007/s00280-014-2660-0

Cited by 10 publications

(23 citation statements)

References 15 publications

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“…It was possible to use McCune's model for analysis combining adult and pediatric busulfan data by including a maturation function. Body weight is correlated with age, and therefore other models for busulfan PopPK analysis generally do not include the maturation of clearance . busulfan clearance is empirically known to decrease over time, and it was 12% lower at Days 2 through 4 than at Day 1 .…”

Section: Discussionmentioning

confidence: 99%

“…Body weight is correlated with age, and therefore other models for busulfan PopPK analysis generally do not include the maturation of clearance. [9][10][11][12][13][14][15][16][17][18][19][20][21]23 busulfan clearance is empirically known to decrease over time, and it was 12% lower at Days 2 through 4 than at Day 1. 21 Long-Boyle et al described busulfan clearance using Michaelis-Menten elimination, 23 and this is the only report that uses Michaelis-Menten elimination.…”

Section: Discussionmentioning

confidence: 99%

“…The use of incorrect population pharmacokinetic (PopPK) modeling strategies for TDM lead to erroneous dosing design, 8 and therefore an appropriate PopPK model is needed. Numerous PopPK model analyses of busulfan have been reported, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] including 3 PopPK analyses in Japanese patients. 9,15,17 In the Japanese PopPK analyses, only a 1-compartment model was used.…”

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confidence: 99%

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Population Pharmacokinetic Analysis of Busulfan in Japanese Pediatric and Adult HCT Patients

Kawazoe

Funaki

Kim

2018

The Journal of Clinical Pharma

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Busulfan is the most common chemotherapy agent used in allogeneic hematopoietic cell transplant (HCT) conditioning regimens. As narrow therapeutic index and interpatient variability exists in the effectiveness and toxicity of conditioning regimens, personalizing intravenous busulfan therapy is desirable. Population pharmacokinetic-based approaches have been applied to therapeutic drug monitoring for the purpose of personalizing therapy. A population pharmacokinetic analysis with the objective of personalizing therapy in Japanese patients was conducted by integrating pediatric patient data with adult patient data. McCune's model, a 2-compartment model that includes maturation of clearance and allometric scaling of clearance and volume of distribution, was used for the analysis. McCune's model could precisely describe the Japanese data, and the estimated parameters were similar to McCune's results for non-Japanese, indicating that there are no racial differences in busulfan pharmacokinetics. Using this model, the plasma concentrations for once-daily dosing were simulated to adapt new dosage regimens for the benefit and convenience of both patients and medical staff. The predicted busulfan concentrations were within the therapeutic range.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Population Pharmacokinetic Analysis of Busulfan in Japanese Pediatric and Adult HCT Patients

Kawazoe

Funaki

Kim

2018

The Journal of Clinical Pharma

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“…40 In addition, a population PK analysis demonstrated that Bu PK can be adequately described by a linear PK model without inter-occasional variability. 48 In this study, more than one-third of patients would have had suboptimal exposure to IV Bu if weight-based dosing alone had been used for conditioning, whereas 95% of subjects achieved the target range of Bu exposure after the introduction of individualized TDM. A pre-conditioning test dose may be more convenient for transplant centers relying on external PK laboratories and can offer another opportunity for TDM on the first day of conditioning if the initial PK results are not evaluable.…”

Section: Discussionmentioning

confidence: 77%

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes

Flowers

Costa

Pasquini

et al. 2016

Biology of Blood and Marrow Transplantation

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Busulfan, cyclophosphamide and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem-cell transplantation (ASCT). This multicenter, phase 2 study examined the safety and efficacy of BuCyE with individually-adjusted busulfan based on pre-conditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients 18–80 years, but was amended due to high early treatment-related mortality (TRM) in patients >65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n=66) or NHL (n=141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n=203), patients >65 years (n=17), and patients ≤65 years (n=186) were 4.5%, 23.5% and 2.7%, respectively. The estimated 2-year PFS was 33% for HL, and 58%, 77% and 43% for diffuse large B-cell lymphoma (DLBCL; n=63), mantle cell lymphoma (MCL; n=29) and follicular lymphoma (FL; n=23), respectively. The estimated 2-year OS was 76% for HL, and 65%, 89% and 89% for DLBCL, MCL and FL, respectively. In the matched analysis, two-year TRM was 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower 2-year PFS with BuCyE, 33% (95% CI: 21–46%) than BEAM, 59% (95% CI: 52–66%), with no difference in TRM or OS. BuCyE provided adequate disease control and safety in B-cell NHL patients ≤ 65 years, but produced worse PFS in HL patients when compared with BEAM.

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“…WT, BSA, IBW, AIBW, BMI, fat-free mass, and normal fat mass are usually considered to be indicators of body size. 40,41 The maturation of CL is a major difference in the PK of busulfan between children and adults, as maturation is directly related to age. 33 Maturation of CL in neonates may be described by both PMA and postnatal age (PNA); however, PMA is a more physiologically appropriate covariate to explain the time course of changes in CL.…”

Section: Discussionmentioning

confidence: 99%

Can Published Population Pharmacokinetic Models of Busulfan Be Used for Individualized Dosing in Chinese Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation? An External Evaluation

Huang

Liu

Ren

et al. 2021

The Journal of Clinical Pharma

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Busulfan is a bifunctional alkylating agent that is widely used before hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (popPK) model for busulfan in Chinese pediatric patients. A systemic external evaluation of 11 published popPK models was conducted in Chinese pediatric patients undergoing HSCT. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE%, median absolute PE%, and percentage of PE% within ±20% and ±30% were calculated in prediction-based diagnostics. Simulation-based diagnostics were conducted through a predictionand variability-corrected visual predictive check and the normalized prediction distribution error. The relative individual prediction error was calculated using Bayesian forecasting with 1 to 3 concentration points. The 1-compartment open linear popPK model, which was built by Su-jin Rhee et al (model H), incorporating the patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other popPK models. In prediction-based diagnostics, the median PE%, percentage of PE% within ±20%, and percentage of PE% within ±30% of model H were 8.48%, 45.35%, and 59.56%, respectively. The normalized prediction distribution error of model H showed that it followed the normal distribution. Based on Bayesian forecasting, model H showed good predictive performance. Thus, model H was the most appropriate model that can be used clinically for individualized dosage adjustments in Chinese pediatric HSCT patients.

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Dosing algorithm revisit for busulfan following IV infusion

Abstract: The proposed dosing algorithm can significantly improve the sub-exposure of Bu. A shortened test PK study duration with reduced PK samples can provide as near as good estimate for Bu CL. A simplified CL estimation method is valid.

Cited by 10 publications

References 15 publications

Population Pharmacokinetic Analysis of Busulfan in Japanese Pediatric and Adult HCT Patients

Population Pharmacokinetic Analysis of Busulfan in Japanese Pediatric and Adult HCT Patients

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes

Can Published Population Pharmacokinetic Models of Busulfan Be Used for Individualized Dosing in Chinese Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation? An External Evaluation

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