Evaluation of two software using Bayesian methods for monitoring exposure and dosing once-daily intravenous busulfan in paediatric patients receiving haematopoietic stem cell transplantation

Lawson, Rachael; Paterson, Lachlan; Fraser, Christopher; Hennig, Stefanie

doi:10.1007/s00280-021-04288-0

Cited by 10 publications

(19 citation statements)

References 43 publications

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“…In 2013, the first overview of available software was published, and new tools have been developed since that review. [16][17][18] Examples of widely used software for TDM with some applications used in the pediatric population are MWPharm (eg, flucloxacillin 19 ), BestDose (eg, teicoplanin 20 ), InsightRx (vancomycin 21 ), NextDose (busulfan 22 ), and Monolix (eg, vancomycin 23 ). The reader is referred to the available literature because this field is developing quickly, and this list will soon be outdated.…”

Section: Tools For Tdmmentioning

confidence: 99%

Therapeutic Drug Monitoring of Antimicrobial Drugs in Neonates: An Opinion Article

Touw

Anker

2022

Therapeutic Drug Monitoring

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Background: Neonatal infections are associated with high morbidity and mortality rates. Optimal treatment of these infections requires knowledge of neonatal pharmacology and integration of neonatal developmental pharmacokinetics (PKs) of antimicrobial drugs in the design of dosing regimens for use with different gestational and postnatal ages. Population PK and pharmacodynamic models are used to personalize the use of these drugs in these fragile patients. The final step to further minimize variability in an individual patient is therapeutic drug monitoring (TDM), where the same population PK/pharmacodynamic models are used in concert with optimally drawn blood samples to further fine-tune therapy. The purpose of this article is to describe the present status and future role of model-based precision dosing and TDM of antimicrobial drugs in neonates. Methods: PubMed was searched for clinical trials or clinical studies of TDM in neonates.Results: A total of 447 articles were retrieved, of which 19 were concerned with antimicrobial drugs. Two articles (one aminoglycoside and one vancomycin) addressed the effects of TDM in neonates. We found that, in addition to aminoglycosides and vancomycin, TDM also plays a role in beta-lactam antibiotics and antifungal drugs.Conclusions: There is a growing awareness that, in addition to aminoglycosides and vancomycin, the use of beta-lactam antibiotics, such as amoxicillin and meropenem, and other classes of antimicrobial drugs, such as antifungal drugs, may benefit from TDM. However, the added value must be shown. New analytical techniques and software development may greatly support these novel developments.

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Section: Tools For Tdmmentioning

confidence: 99%

Therapeutic Drug Monitoring of Antimicrobial Drugs in Neonates: An Opinion Article

Touw

Anker

2022

Therapeutic Drug Monitoring

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“…10 Application of a population model describing changes in CL of busulfan over time in a Bayesian forecasting program could assist with making dosage adjustments. 13,20,21 A recent review of published non-linear mixed effects (NLME) models for i.v. busulfan in children identified 21 studies 10 ; however, few focused on once-daily therapy or included samples from all 4 days of treatment to enable characterization of temporal changes in busulfan CL.…”

Section: How Might This Change Drug Discovery Development And/or Ther...mentioning

confidence: 99%

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

Lawson

Staatz

Fraser

et al. 2022

CPT Pharmacom & Syst Pharma

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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.

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“…Four times daily regimen have enabled to adjust the dose of Bu from the third dose onwards during the 1st day of Bu (depending on access to a biomedical analysis laboratory), which is not feasible with once daily dosing. However, TDM-guided dose adjustment from the 2nd day of Busulfan infusion is feasible with once-daily dosing and allows cumulative exposure to be readily estimated (75). The less commonly used twice daily Bu schedule (every 12 h administration, eight doses) allows dose adjustments from the 2nd day of Bu treatment, whilst reducing the workload associated with the four times daily dosing.…”

Section: Busulfan Administration Schedulementioning

confidence: 99%

“…Several studies have also included an age-based metric to describe the ontogeny and maturation of Busulfan clearance. Such a model has been shown to result in accurate PK predictions and selection of the first dose in paediatric patients (75,(101)(102)(103).…”

Section: Getting the First Dose Of Busulfan Right: First Dose Personalizationmentioning

confidence: 99%

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

et al. 2021

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Total-body irradiation (TBI) based conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT) is generally regarded as the gold-standard for children >4 years of age with acute lymphoblastic leukaemia (ALL). Retrospective studies in the 1990's suggested better survival with irradiation, confirmed in a small randomised, prospective study in the early 2000's. Most recently, this was reconfirmed by the early results of the large, randomised, international, phase III FORUM study published in 2020. But we know survivors will suffer a multitude of long-term sequelae after TBI, including second malignancies, neurocognitive, endocrine and cardiometabolic effects. The drive to avoid TBI directs us to continue optimising irradiation-free, myeloablative conditioning. In chemotherapy-based conditioning, the dominant myeloablative effect is provided by the alkylating agents, most commonly busulfan or treosulfan. Busulfan with cyclophosphamide is a long-established alternative to TBI-based conditioning in ALL patients. Substituting fludarabine for cyclophosphamide reduces toxicity, but may not be as effective, prompting the addition of a third agent, such as thiotepa, melphalan, and now clofarabine. For busulfan, it's wide pharmacokinetic (PK) variability and narrow therapeutic window is well-known, with widespread use of therapeutic drug monitoring (TDM) to individualise dosing and control the cumulative busulfan exposure. The development of first-dose selection algorithms has helped achieve early, accurate busulfan levels within the targeted therapeutic window. In the future, predictive genetic variants, associated with differing busulfan exposures and toxicities, could be employed to further tailor individualised busulfan-based conditioning for ALL patients. Treosulfan-based conditioning leads to comparable outcomes to busulfan-based conditioning in paediatric ALL, without the need for TDM to date. Future PK evaluation and modelling may optimise therapy and improve outcome. More recently, the addition of clofarabine to busulfan/fludarabine has shown encouraging results when compared to TBI-based regimens. The combination shows activity in ALL as well as AML and deserves further evaluation. Like busulfan, optimization of chemotherapy conditioning may be enhanced by understanding not just the PK of clofarabine, fludarabine, treosulfan and other agents, but also the pharmacodynamics and pharmacogenetics, ideally in the context of a single disease such as ALL.

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Evaluation of two software using Bayesian methods for monitoring exposure and dosing once-daily intravenous busulfan in paediatric patients receiving haematopoietic stem cell transplantation

Cited by 10 publications

References 43 publications

Therapeutic Drug Monitoring of Antimicrobial Drugs in Neonates: An Opinion Article

Therapeutic Drug Monitoring of Antimicrobial Drugs in Neonates: An Opinion Article

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

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

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