Dataset Information

Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population.

ABSTRACT: Introduction:Population pharmacokinetic (PK) studies demonstrate model-based dosing for busulfan that incorporates body size and age improve clinical target attainment as compared to weight-based regimens. Recently, for clinical dosing of busulfan and TDM, our institution transitioned to a cloud-based clinical decision support tool (www.insight-rx.com). The goal of this study was to assess the dose decision tool for the achievement of target exposure of busulfan in children undergoing hematopoietic cell transplantation (HCT). Patients and Methods:Patients (N = 188) were grouped into cohorts A, B, or C based on the method for initial dose calculation and estimation of AUC: Cohort A: Initial doses were based on the conventional dosing algorithm (as outlined in the manufacturers' package insert) and non-compartmental analysis (NCA) estimation using the trapezoidal rule for estimation of AUC following TDM. Cohort B: Initial doses for busulfan were estimated by a first-generation PK model and NCA estimation of AUC following TDM. Cohort C: Initial doses were calculated by an updated, second-generation PK model available in the dose decision tool with an estimation of AUC following TDM. Results:The percent of individuals achieving the exposure target at the time of first PK collection was higher in subjects receiving initial doses provided by the model-informed precision dosing platform (cohort C, 75%) versus subjects receiving initial doses based on either of the two other approaches (conventional guidelines/cohort A, 25%; previous population PK model and NCA parameter estimation, cohort B, 50%). Similarly, the percent of subjects achieving the targeted cumulative busulfan exposure (cAUC) in cohort C was 100% vs. 66% and 88% for cohort A and B, respectively. For cAUC, the variability in the spread of target attainment (%CV) was low at 4.1% for cohort C as compared to cohort A (14.8%) and cohort B (17.1%). Conclusion:Achievement of goal exposure early on in treatment was improved with the updated model for busulfan and the Bayesian platform. Model-informed dosing and TDM utilizing a Bayesian-based platform provides a significant advantage over conventional guidelines for the achievement of goal cAUC exposure.

SUBMITTER: Shukla P

PROVIDER: S-EPMC7351521 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population.

Shukla Praveen P Goswami Srijib S Keizer Ron J RJ Winger Beth Apsel BA Kharbanda Sandhya S Dvorak Christopher C CC Long-Boyle Janel J

Frontiers in pharmacology 20200702

<h4>Introduction</h4>Population pharmacokinetic (PK) studies demonstrate model-based dosing for busulfan that incorporates body size and age improve clinical target attainment as compared to weight-based regimens. Recently, for clinical dosing of busulfan and TDM, our institution transitioned to a cloud-based clinical decision support tool (www.insight-rx.com). The goal of this study was to assess the dose decision tool for the achievement of target exposure of busulfan in children undergoing he ...[more]

PMID: 32714184

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Project description:Background and objectiveThe immunosuppressant everolimus is increasingly applied in renal transplantation. Its extensive pharmacokinetic variability necessitates therapeutic drug monitoring, typically based on whole-blood trough concentrations (C0). Unfortunately, therapeutic drug monitoring target attainment rates are often unsatisfactory and patients with on-target exposure may still develop organ rejection. As everolimus displays erythrocyte partitioning, haematocrit-normalised whole-blood exposure has been suggested as a more informative therapeutic drug monitoring marker. Furthermore, model-informed precision dosing has introduced options for more sophisticated dose adaptation. We have previously developed a mechanistic population pharmacokinetic model, which described everolimus plasma pharmacokinetics and enabled estimation of haematocrit-normalised whole-blood exposure. Here, we externally evaluated this model for its utility for model-informed precision dosing.MethodsThe retrospective dataset included 4123 pharmacokinetic observations from routine clinical therapeutic drug monitoring in 173 renal transplant recipients. Model appropriateness was confirmed with a visual predictive check. A fit-for-purpose analysis was conducted to evaluate whether the model accurately and precisely predicted a future C0 or area under the concentration-time curve (AUC) from prior pharmacokinetic observations. Bias and imprecision were expressed as the mean percentage prediction error (MPPE) and mean absolute percentage prediction error (MAPE), stratified on 6 months post-transplant. Additionally, we compared dose adaptation recommendations of conventional C0-based therapeutic drug monitoring and C0- or AUC-based model-informed precision dosing, and assessed the percentage of differences between observed and haematocrit-normalised C0 (∆C0) and AUC (∆AUC) exceeding ± 20%.ResultsThe model showed adequate accuracy and precision for C0 and AUC prediction at ≤ 6 months (MPPEC0: 8.1 ± 2.5%, MAPEC0: 26.8 ± 2.1%; MPPEAUC: - 9.7 ± 5.1%, MAPEAUC: 13.3 ± 3.9%) and > 6 months post-transplant (MPPEC0: 4.7 ± 2.0%, MAPEC0: 25.4 ± 1.4%; MPPEAUC: - 0.13 ± 4.8%, MAPEAUC: 13.3 ± 2.8%). On average, dose adaptation recommendations derived from C0-based and AUC-based model-informed precision dosing were 2.91 ± 0.01% and 13.7 ± 0.18% lower than for conventional C0-based therapeutic drug monitoring at ≤ 6 months, and 0.93 ± 0.01% and 3.14 ± 0.04% lower at > 6 months post-transplant. The ∆C0 and ∆AUC exceeded ± 20% on 13.6% and 14.3% of occasions, respectively.ConclusionsWe demonstrated that our population pharmacokinetic model was able to accurately and precisely predict future everolimus exposure from prior pharmacokinetic measurements. In addition, we illustrated the potential added value of performing everolimus therapeutic drug monitoring with haematocrit-normalised whole-blood concentrations. Our results provide reassurance to implement this methodology in clinical practice for further evaluation.

Project description:Model-informed precision dosing (MIPD) software tools are used to optimize dosage regimens in individual patients, aiming to achieve drug exposure targets associated with desirable clinical outcomes. Over the last few decades, numerous MIPD software tools have been developed. However, they have still not been widely integrated into clinical practice. This study focuses on identifying the requirements for and evaluating the performance of the currently available MIPD software tools. First, a total of 22 experts in the field of precision dosing completed a web survey to assess the importance (from 0; do not agree at all, to 10; completely agree) of 103 pre-established software tool criteria organized in eight categories: user-friendliness and utilization, user support, computational aspects, population models, quality and validation, output generation, privacy and data security, and cost. Category mean ± pooled standard deviation importance scores ranged from 7.2 ± 2.1 (user-friendliness and utilization) to 8.5 ± 1.8 (privacy and data security). The relative importance score of each criterion within a category was used as a weighting factor in the subsequent evaluation of the software tools. Ten software tools were identified through literature and internet searches: four software tools were provided by companies (DoseMeRx, InsightRX Nova, MwPharm++, and PrecisePK) and six were provided by non-company owners (AutoKinetics, BestDose, ID-ODS, NextDose, TDMx, and Tucuxi). All software tools performed well in all categories, although there were differences in terms of in-built software features, user interface design, the number of drug modules and populations, user support, quality control, and cost. Therefore, the choice for a certain software tool should be made based on these differences and personal preferences. However, there are still improvements to be made in terms of electronic health record integration, standardization of software and model validation strategies, and prospective evidence for the software tools' clinical and cost benefits.

Dataset Information

Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population.

Publications

Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population.

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