Optimal Once-Daily Busulfan Administration in Pediatric Patients: A Simulation-Based Investigation of Intravenous Infusion Times.

Purpose: Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity. Patients and methods: Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens. Results: Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion. Conclusion: While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.

Limited Sampling Strategies for Estimating Busulfan Area Under the Concentration-Time Curve: Based on Peak and Trough Concentrations in Saliva.

Therapeutic drug monitoring for busulfan is currently performed by multiple plasma sampling. Saliva is considered a noninvasive therapeutic drug monitoring matrix. This study aimed to investigate intravenous busulfan pharmacokinetics (PK) in plasma and saliva, and establish a limited sampling strategy (LSS) for predicting the area under the concentration-time curve from time zero to infinity in plasma (AUC0-∞,p) by using saliva samples. Therefore, the PK of busulfan was studied in 37 Chinese patients. Pearson correlation analysis was used to evaluate the correlation between the AUC of busulfan in plasma and saliva. LSS models were established by the multiple linear regression analysis. The prediction error, the mean prediction error, and the root mean square error were used to evaluate the predictive accuracy. The agreement between the predicted and observed AUC0-∞ in saliva was investigated by the intraclass correlation coefficient and Bland-Altman analysis. The accuracy and robustness of the models were evaluated by using the bootstrap procedure. The result of PK analysis 62.2% of patients (23/37) was within the target range of AUC0-∞,p . A good correlation between saliva and plasma busulfan AUC0-∞ was observed (r = 0.63, p < .01). The bias and precision of the models 7 and 13 were less than 15%. The intraclass correlation coefficient exceeded 0.9, and the limits of agreement were within ±15%. The 2-point LSS model in saliva is a convenient and desirable approach to predict the AUC0-∞ of 4 times daily intravenous busulfan in plasma, which can be used to design personalized dosing for busulfan.

PEG 400 Ion Suppression in Busulfan Detection by High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Busulfan (Bu), an alkylating agent commonly used in chemotherapy and transplantation, exhibits high intraindividual pharmacokinetic variability and possible time-dependent variations in clearance, which complicate therapeutic drug monitoring. Numerous analytical methods have been developed to reduce analysis time and facilitate timely decision-making regarding treatment changes; however, the validation procedures rarely involve analysis of potentially interfering excipients. Macrogol 400 (PEG 400) should be considered as a possible interfering agent in the detection of plasma Bu levels, especially as an ionization suppressor. METHODS: Six intravenous formulations of Bu were compared with identify at least 1 common excipient (PEG 400). During the 176 therapeutic drug monitoring analyses of Bu, one of the PEG 400 specific mass-to-charge ratio transitions was determined using an instrumental method. After coelution with Bu and its internal standard (Bu-d8) was confirmed, all analyses were repeated using a different experimental setup free of ion suppression induced by PEG. The concentration-time profile of PEG 400 was also analyzed. RESULTS: The area under the curve obtained from the 2 data sets was compared and analyzed using Lin concordance correlation coefficient and Bland-Altman plot analysis. The results from the 2 analytical methods were comparable: PEG 400 negatively affected the Bu-d8 coefficient of variation but not the Bu/Bu-d8 ratio. CONCLUSIONS: The possible interference of PEG 400 should be thoroughly investigated, especially with respect to analytical methods that cannot be supported by correction of the stable isotopically labeled internal standard analog.

Limited Sampling Strategy Using End of Infusion and Six-Hour Concentrations Overestimates Intravenous Busulfan Clearance Compared With Standard Six-Point Sampling in Hematopoietic Stem Cell Transplant Patients.

BACKGROUND: Therapeutic drug monitoring for busulfan (Bu) is important to improve outcomes of hematopoietic stem cell transplantation. However, standard therapeutic drug monitoring requires multiple samples and is inconvenient, labor-intensive, and costly. Accordingly, a limited sampling strategy (LSS) was evaluated, using 2-point sampling at end of infusion and at 6 hours, and the area-under-the-curve and Bu clearances (CLs) were compared with the results obtained from the standard sampling strategy (SSS) using 5-6 samples. METHOD: The analysis was based on retrospective clinical data from 202 patients receiving intravenous Bu before hematopoietic stem cell transplantation for malignant or nonmalignant conditions. Bu plasma concentrations were measured via liquid chromatography tandem-mass spectrometry, and pharmacokinetic parameters were calculated using the PKCNA package in R program. RESULT: A total of 502 doses were analyzed by applying SSS and LSS. Using the modified Bland-Altman plot, the mean percentage difference in CL between the SSS and LSS estimates of Bu 6-hourly regimen was -41% (Limits: -53% and -30%). In the once daily regimen, the mean difference in CL between the 2 strategies on the modified Bland-Altman plot was -22% (Limits: -66% and +22%). CONCLUSIONS: The Bu CL values estimated based on the BU concentration at end of infusion and at 6 hours postinfusion were significantly higher than the values obtained via the SSS.

Population Pharmacokinetic Model of Intravenous Busulfan in Hematopoietic Cell Transplantation: Systematic Review and Comparative Simulations.

BACKGROUND: Busulfan is commonly used in the chemotherapy prior to hematopoietic cell transplantation (HCT). Busulfan has a narrow therapeutic window and a well-established exposure-response relationship with important clinical outcomes. Model-informed precision dosing (MIPD) based on population pharmacokinetic (popPK) models has been implemented in the clinical settings. We aimed to systematically review existing literature on popPK models of intravenous busulfan. METHODS: We systematically searched Ovid MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science databases from inception to December 2022 to identify original popPK models (nonlinear mixed-effect modeling) of intravenous busulfan in HCT population. Model-predicted busulfan clearance (CL) was compared using US population data. RESULTS: Of the 44 eligible popPK studies published since 2002, 68% were developed predominantly in children, 20% in adults, and 11% in both children and adults. The majority of the models were described using first-order elimination or time-varying CL (69% and 26%, respectively). All but three included a body-size descriptor (e.g., body weight, body surface area). Other commonly included covariates were age (30%) and GSTA1 variant (15%). Median between-subject and between-occasion variabilities of CL were 20% and 11%, respectively. Between-model variabilities in predicted median CL were < 20% in all of the weight tiers (10-110 kg) in the simulation based on US population data. CONCLUSION: Busulfan PK is commonly described using a first-order elimination or time-varying CL. A simple model with limited covariates were generally sufficient to attain relatively small unexplained variabilities. However, therapeutic drug monitoring may still be necessary to attain a narrow target exposure.

Saliva as a noninvasive sampling matrix for therapeutic drug monitoring of intravenous busulfan in Chinese patients undergoing hematopoietic stem cell transplantation: A prospective population pharmacokinetic and simulation study.

Therapeutic drug monitoring (TDM) of busulfan (BU) is currently performed by plasma sampling in patients undergoing hematopoietic stem cell transplantation (HSCT). Saliva samples are considered a noninvasive TDM matrix. Currently, no salivary population pharmacokinetics (PopPKs) model for BU available. This study aimed to develop a PopPK model that can describe the relationship between plasma and saliva kinetics in patients receiving intravenous BU. The performance of the model in predicting the area under the concentration-time curve at steady state (AUCss ) based on saliva samples is evaluated. Sixty-six patients with HSCT were recruited and administered 0.8 mg/kg BU intravenously. A PopPK model for saliva and plasma was developed using the nonlinear mixed effects model. Bayesian maximum a posteriori (MAP) optimization was used to estimate the model's predictive performance. Plasma and saliva PKs were adequately described with a one-compartment model and a scaled central compartment. Body surface area correlated positively with both clearance and apparent volume of distribution (Vd), whereas alkaline phosphatase correlated negatively with Vd. Simulations demonstrated that the percentage root mean squared prediction error and lower and upper limits of agreements reduced to 10.02% and -16.96% to 22.86% based on five saliva samples. Saliva can be used as an alternative matrix to plasma in TDM of BU. The AUCss can be predicted from saliva concentration by Bayesian MAP optimization, which can be used to design personalized dosing for BU.

Population pharmacokinetic modeling of treosulfan and rationale for dose recommendation in children treated for conditioning prior to allogeneic hematopoietic stem cell transplantation.

Intravenously infused treosulfan was evaluated in adult and pediatric patients for conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. A population pharmacokinetic (PK) model was initially developed on 116 adult and pediatric PK profiles from historical trials, to support treosulfan dose recommendations for children in 2 prospective trials. The aim was to assess and update the initial population PK model by inclusion of additional 83 pediatric PK profiles from these 2 trials. The final population PK model was 2-compartmental with dosing in the central compartment, linear elimination, and inter-compartmental clearance. Inter-individual variability was included on clearance (CL), central volume (V1), peripheral volume (V2), and inter-compartmental clearance (Q). The final model described an effect of the body surface area (BSA) on CL, V1, V2, and Q. The final model resulted in a modified dose recommendation for children and advises treosulfan doses of 10 g/m2, 12 g/m2, and 14 g/m2 for BSAs of <0.4 m2, ≥0.4 to <0.9 m2, and ≥0.9 m2, respectively. This simplified BSA-dependent dose recommendation was developed for children, ensuring a well comparable treosulfan exposure as a dose of 14 g/m2 in adults - irrespective of their age and without applying individual therapeutic drug monitoring.

Predicting busulfan exposure in patients undergoing hematopoietic stem cell transplantation using machine learning techniques.

PURPOSE: This study aimed to establish an optimal model to predict the busulfan (BU) area under the curve at steady state (AUCss) by using machine learning (ML). PATIENTS AND METHODS: Seventy-nine adult patients (age ≥18 years) who received BU intravenously and underwent therapeutic drug monitoring from 2013 to 2021 at Fujian Medical University Union Hospital were enrolled in this retrospective study. The whole dataset was divided into a training group and test group at the ratio of 8:2. BU AUCss were considered as the target variable. Nine different ML algorithms and one population pharmacokinetic (pop PK) model were developed and validated, and their predictive performance was compared. RESULTS: All ML models were superior to the pop PK model (R2 = 0.751, MSE = 0.722, 14 and RMSE = 0.830) in model fitting and had better predictive accuracy. The ML model of BU AUCss established through support vector regression (SVR) and gradient boosted regression trees (GBRT) had the best predictive ability (R2 = 0.953 and 0.953, MSE = 0.323 and 0.326, and RMSE = 0.423 and 0.425). CONCLUSION: All the ML models can potentially be used to estimate BU AUCss with the aim of facilitating rational use of BU on the individualized level, especially models built by SVR and GBRT algorithms.

Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test-Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients.

Busulfan is an alkylating agent used as part of conditioning chemotherapy regimens prior to allogeneic hematopoietic cell transplant (allo-HCT). Pharmacokinetic (PK)-guided test-dose strategies have been shown to improve the number of patients achieving busulfan exposure goals and improve clinical outcomes. However, current practices require extensive PK sampling. In this study, PK data were retrospectively collected from busulfan drug monitoring records from adult allo-HCT recipients who received once-daily intravenous busulfan at the University of North Carolina Medical Center (UNCMC). A population pharmacokinetic (popPK) model was developed to identify sources of interindividual variability and evaluate alternative PK sampling strategies. A 2-compartment model, with covariate effects of actual body weight and sex, best described the data. The typical value of clearance for an 83 kg male was estimated to be 11.21 L/h. Fifty-nine percent of allo-HCT recipients were estimated to have met the UNCMC institutional myeloablative conditioning (MAC) exposure goal based on model post hoc estimates of clearance using all PK samples obtained following MAC dosing. Fifty-seven percent of patients were estimated to have met this goal based on post hoc estimates using a single PK sample. Our results indicate once-daily, intravenous busulfan PK in adult allo-HCT recipients receiving MAC dosing can be reasonably described by a popPK model, and the use of a sparse PK sampling strategy may be feasible for determining target exposure attainment following MAC dosing. Use of a popPK model and sparse PK sampling strategy to carry out busulfan test-dose procedures could reduce health care costs and inconvenience to patients.

Busulfan Interlaboratory Proficiency Testing Program Revealed Worldwide Errors in Drug Quantitation and Dose Recommendations.

BACKGROUND: The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively. METHODS: A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with ±15% for busulfan concentrations and ±10% for busulfan plasma exposure. The dose recommendations were deemed accurate. RESULTS: Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values. CONCLUSIONS: The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.

Effect of pharmacokinetics and pharmacogenomics in adults with allogeneic hematopoietic cell transplantation conditioned with Busulfan.

Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at -52 or -69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at -52 (rs3957356) and -69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.

Individualizing busulfan dose in specific populations and evaluating the risk of pharmacokinetic drug-drug interactions.

INTRODUCTION: Busulfan is an alkylating agent widely used in the conditioning of hematopoietic stem cell transplantation possessing a complex metabolism and a large interindividual and intra-individual variability, especially in children. Combined with the strong rationale of busulfan PK/PD relationships, factors altering its clearance (e.g. weight, age, and GST-A genetic polymorphism mainly) can also affect clinical outcomes. AREAS COVERED: This review aims to provide an overview of the current knowledge on busulfan pharmacokinetics, its pharmacokinetics variabilities in pediatric populations, drug-drug interactions (DDI), and their consequences regarding dose individualization. This review was based on medical literature up until October 2021. EXPERT OPINION: To ensure effective busulfan exposure in pediatrics, different weight-based nomograms have been established to determine busulfan dosage and provided improved results (65-80% of patients correctly exposed). In addition to nomograms, therapeutic drug monitoring (TDM) of busulfan measuring plasmatic concentrations to estimate busulfan pharmacokinetic parameters can be used. TDM is now widely carried out in routine practices and aims to ensure the targeting of the reported therapeutic windows by individualizing busulfan dosing based on the clearance estimations from a previous dose.

Evaluation of treosulfan cumulative exposure in paediatric patients through population pharmacokinetics and dosing simulations.

AIM: To investigate the pharmacokinetics (PK) of intravenous treosulfan in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT) for a broad range of diseases and to explore the impact of different dosing regimens on treosulfan exposure (area under the concentration-time curve, AUC0→∞ ) through dosing simulations. METHODS: A prospective multicentre PK study was conducted using treosulfan concentration data (n = 423) collected from 53 children (median age 3.5, range 0.2-17.0 years) receiving three daily age-guided doses (10-14 g/m2 ). Population PK modelling was performed using NONMEM software, utilising a stepwise forward selection backward elimination method and likelihood-ratio test for screening covariates to describe PK variability. Monte Carlo simulation was used to generate patient PK data for 10 000 virtual paediatric patients and cumulative AUC0→∞ values were evaluated using age, body surface area (BSA) and model-based dosing regimens, targeting 4800 mg*h/L. RESULTS: Treosulfan concentration data were described using a one-compartment PK model with first-order elimination. Population mean (95% CI) estimates for clearance (CL) and volume of distribution (V) were 16.3 (14.9-18.1) L/h and 41.9 (38.8-45.1) L, respectively. Allometrically scaled body weight was the best covariate descriptor for CL and V, and maturational age further explained variability in CL. Dosing simulations indicated that in young patient groups (<2 years), a model-based dosing regimen more accurately achieved the target AUC0→∞ (58.3%) over the age (42.6%) and BSA-based (51.3%) regimens. CONCLUSION: Treosulfan disposition was described through allometric body weight and maturational age descriptors. Model-informed dosing is recommended for patients under 2 years. Treosulfan PK parameters and AUC0→∞ were not influenced by patient disease.

Population pharmacokinetic model for once-daily intravenous busulfan in pediatric subjects describing time-associated clearance.

This study aimed to characterize the population pharmacokinetics (PK) of busulfan focusing on how busulfan clearance (CL) changes over time during once-daily administration and assess different methods for measuring busulfan exposure and the ability to achieve target cumulative exposure under different dosing adjustment scenarios in pediatric stem cell transplantation recipients. Daily serial blood sampling was performed and concentration-time data were analyzed using a nonlinear mixed-effects approach. The developed PK model was used to assess achievement of target exposure under six dose-adjustment scenarios based on simulations performed in RStudio (RxODE package)®. A total of 2491 busulfan plasma concentration-time measurements were collected from 95 patients characterizing 379 dosing days. A two-compartment model with time-associated CL best described the data with a typical CL of 14.5 L/h for an adult male with 62 kg normal fat mass (NFM; equivalent to 70 kg total body weight), typical volume of distribution central compartment (V1) of 40.6 L/59 kg NFM (equivalent to 70 kg total body weight), and typical volume of distribution peripheral compartment of 3.57 L/62 kg NFM. Model interindividual variability in CL and V1 was 14.7% and 34.9%, respectively, and interoccasional variability in CL was 6.6%. Patient size described by NFM, a maturation component, and time since start of treatment significantly influenced CL. Simulations demonstrated that using model-based exposure estimates with each dose, and either a proportional dose-adjustment calculation or model-based calculated individual CL estimates to support dose adjustments, increased proportion of subjects attaining cumulative exposure within 5% of target compared with using noncompartmental analysis (100% vs. 0%). A time-associated reduction in CL during once-daily busulfan treatment was described.

Impact of Glutathione S-Transferase Polymorphisms on Busulfan Pharmacokinetics and Outcomes of Hematopoietic Stem Cell Transplantation.

BACKGROUND: Busulfan (Bu) is an alkylating drug used in many preparative regimens before hematopoietic stem cell transplantation (HSCT). It is conjugated in the liver mainly by glutathione S-transferase isoenzyme A1-1 ( GSTA1 ). Genetic polymorphisms in these isoenzymes may affect the pharmacokinetics of Bu and the clinical outcomes of HSCT. This study aimed to assess the impact of glutathione S-transferase ( GST ) genetic polymorphisms on the clearance of Bu and the clinical outcomes of patients undergoing HSCT. METHODS: This single-center retrospective study included patients who received IV Bu before HSCT at Sultan Qaboos University Hospital (SQUH), Oman from January 2003 to October 2016. Genotyping for polymorphisms was performed for GSTM1 , GSTT1 , GSTA1 , and GSTP1 . Each GST polymorphism was analyzed for its impact on Bu clearance and HSCT outcomes. RESULTS: A total of 135 patients were included. The mean Bu clearance was 3.7 ± 0.98 mL/min/kg. Patients with GSTA1 A-513G heterozygosity (AG) were found to have a higher incidence of graft loss ( P = 0.006). Homozygous double null of GSTM1 and GSTT1 was associated with a higher incidence of acute graft versus host disease ( P = 0.04). Double non-null GSTM1 and GSTT1 and non-null GSTM1 increased the risk of mortality ( P = 0.034 and 0.021, respectively). CONCLUSIONS: GST genotyping before HSCT may predict HSCT outcomes. The results of this preliminary retrospective study need to be confirmed in a larger prospective study.

Fixed-dose administration and pharmacokinetically guided adjustment of busulfan dose for patients undergoing hematopoietic stem cell transplantation: a meta-analysis and cost-effectiveness analysis.

This study aims to evaluate the efficacy, safety, and long-term cost-effectiveness of fixed-dose busulfan (Bu) administration and pharmacokinetically (PK) guided adjustment of Bu dose for patients who underwent hematopoietic stem cell transplantation. The efficacy and safety of both dosing strategies were compared using a systematic review and meta-analysis. A Markov model was used in estimating relevant cost and health outcomes from the perspective of the health system. The primary outcomes of interest were lifetime cost, quality adjusted life-years (QALYs) gained, and incremental cost-effectiveness ratio (ICER) in dollar per QALY gained. Results showed that progression-free survival and overall survival in the PK-guided group were higher than that in the fixed-dose group, and the PK-guided group was associated with low non-relapse mortality and relapse rate. In contrast to safety, the incidence of acute graft-versus-host disease (GVHD) was the same in the two groups (P > 0.05). Cost-effectiveness analysis showed that the QALY of the PK-guided group (12.8135 QALYs and $582,475.07) increased by 2.0609 relative to that in the fixed-dose group (10.7526 QALYs and $562,833.20), and the ICER was $9530.72/QALY. One-way and probability sensitivity analyses confirmed the reliability of the results. In conclusion, the PK-guided approach has higher efficacy and is safer.

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

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 prediction- and 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.

Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation.

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Characterization of drug-drug interactions on the pharmacokinetic disposition of busulfan in paediatric patients during haematopoietic stem cell transplantation conditioning.

AIM: The study objective was to develop a population pharmacokinetic model for busulfan to comprehensively examine drug-drug interactions in paediatric patients undergoing haematopoietic stem cell transplantation. Currently, there is limited evidence to substantiate potential drug-drug interactions with busulfan. METHODS: This retrospective study population was comprised of 250 patients receiving, on average, 0.8 mg/kg intravenous busulfan as pretreatment. All model analyses were conducted using nonlinear mixed effects modelling in Pumas v2.0. The metabolic pathways of primary interest were glutathione conjugation and cytochrome P450 (CYP) activity. Concomitant medications were categorized as CYP inhibitors, inducers or glutathione S-transferase depleters, and included in the model as conditional covariates. A bootstrap simulation and visual predictive check were conducted to qualify the final model. RESULTS: The final 1-compartment model incorporates covariates of weight and age in relation to their effects on both total body clearance and volume of distribution. The estimated typical values of clearance and volume were 1.138 L/h (CI: 1.095-1.179 L/h) and 3.527 L (CI: 3.418-3.621 L), respectively. No significant changes in clearance were observed when medications that alter proposed hepatic and metabolic pathways of busulfan were coadministered. CONCLUSION: To the best of our knowledge, this is the largest single centre study of busulfan in children and the first to quantify the maturation effect of both clearance and volume. This study could not demonstrate a difference in busulfan clearance when comparing patients who received medications that alter the glutathione S-transferase, CYP3A4 or CYP2C9 pathway to those who did not.

Evaluation of the Robustness of Therapeutic Drug Monitoring Coupled with Bayesian Forecasting of Busulfan with Regard to Inaccurate Documentation.

BACKGROUND: Inaccurate documentation of sampling and infusion times is a potential source of error in personalizing busulfan doses using therapeutic drug monitoring (TDM). Planned times rather than the actual times for sampling and infusion time are often documented. Therefore, this study aimed to evaluate the robustness of a limited sampling TDM of busulfan with regard to inaccurate documentation. METHODS: A pharmacometric analysis was conducted in NONMEM® 7.4.3 and "R" by performing stochastic simulation and estimation with four, two and one sample(s) per patient on the basis of a one-compartment- (1CMT) and two-compartment (2CMT) population pharmacokinetic model. The dosing regimens consisted of i.v. busulfan (0.8 mg/kg) every 6 h (Q6H) or 3.2 mg/kg every 24 h (Q24H) with a 2 h- and 3 h infusion time, respectively. The relative prediction error (rPE) and relative root-mean-square error (rRmse) were calculated in order to determine the accuracy and precision of the individual AUC estimation. RESULTS: A noticeable impact on the estimated AUC based on a 1CMT-model was only observed if uncertain documentation reached ± 30 min (1.60% for Q24H and 2.19% for Q6H). Calculated rPEs and rRmse for Q6H indicate a slightly lower level of accuracy and precision when compared to Q24H. Spread of rPE's and rRmse for the 2CMT-model were wider and higher compared to estimations based on a 1CMT-model. CONCLUSIONS: The estimated AUC was not affected substantially by inaccurate documentation of sampling and infusion time. The calculated rPEs and rRmses of estimated AUC indicate robustness and reliability for TDM of busulfan, even in presence of erroneous records.