Dataset Information

Continuous Learning in Model-Informed Precision Dosing: A Case Study in Pediatric Dosing of Vancomycin.

ABSTRACT: Model-informed precision dosing (MIPD) leverages pharmacokinetic (PK) models to tailor dosing to an individual patient's needs, improving attainment of therapeutic drug exposure targets and thus potentially improving drug efficacy or reducing adverse events. However, selection of an appropriate model for supporting clinical decision making is not trivial. Error or bias in dose selection may arise if the selected model was developed in a population not fully representative of the intended MIPD population. One previously proposed approach is continuous learning, in which an initial model is used in MIPD and then updated as additional data becomes available. In this case study of pediatric vancomycin MIPD, the potential benefits of the continuous learning approach are investigated. Five previously published models were evaluated and found to perform adequately in a data set of 273 pediatric patients in the intensive care unit. Additionally, two predefined simple PK models were fitted on separate populations of 50-350 patients in an approach mimicking clinical implementation of automated continuous learning. With these continuous learning models, prediction error using population PK parameters could be reduced by 2-13% compared with previously published models. Sample sizes of at least 200 patients were found suitable for capturing the interindividual variability in vancomycin at this institution, with limited benefits of larger data sets. Although comprised mostly of trough samples, these sparsely sampled routine clinical data allowed for reasonable estimation of simulated area under the curve (AUC). Together, these findings lay the foundations for a continuous learning MIPD approach.

SUBMITTER: Hughes JH

PROVIDER: S-EPMC7839485 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Continuous Learning in Model-Informed Precision Dosing: A Case Study in Pediatric Dosing of Vancomycin.

Hughes Jasmine H JH Tong Dominic M H DMH Lucas Sarah Scarpace SS Faldasz Jonathan D JD Goswami Srijib S Keizer Ron J RJ

Clinical pharmacology and therapeutics 20201121 1

Model-informed precision dosing (MIPD) leverages pharmacokinetic (PK) models to tailor dosing to an individual patient's needs, improving attainment of therapeutic drug exposure targets and thus potentially improving drug efficacy or reducing adverse events. However, selection of an appropriate model for supporting clinical decision making is not trivial. Error or bias in dose selection may arise if the selected model was developed in a population not fully representative of the intended MIPD po ...[more]

PMID: 33068298

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Project description:Treatment response variability across patients is a common phenomenon in clinical practice. For many drugs this inter-individual variability does not require much (if any) individualisation of dosing strategies. However, for some drugs, including chemotherapies and some monoclonal antibody treatments, individualisation of dosages are needed to avoid harmful adverse events. Model-informed precision dosing (MIPD) is an emerging approach to guide the individualisation of dosing regimens of otherwise difficult-to-administer drugs. Several MIPD approaches have been suggested to predict dosing strategies, including regression, reinforcement learning (RL) and pharmacokinetic and pharmacodynamic (PKPD) modelling. A unified framework to study the strengths and limitations of these approaches is missing. We develop a framework to simulate clinical MIPD trials, providing a cost and time efficient way to test different MIPD approaches. Central for our framework is a clinical trial model that emulates the complexities in clinical practice that challenge successful treatment individualisation. We demonstrate this framework using warfarin treatment as a use case and investigate three popular MIPD methods: 1. Neural network regression; 2. Deep RL; and 3. PKPD modelling. We find that the PKPD model individualises warfarin dosing regimens with the highest success rate and the highest efficiency: 75.1% of the individuals display INRs inside the therapeutic range at the end of the simulated trial; and the median time in the therapeutic range (TTR) is 74%. In comparison, the regression model and the deep RL model have success rates of 47.0% and 65.8%, and median TTRs of 45% and 68%. We also find that the MIPD models can attain different degrees of individualisation: the Regression model individualises dosing regimens up to variability explained by covariates; the Deep RL model and the PKPD model individualise dosing regimens accounting also for additional variation using monitoring data. However, the Deep RL model focusses on control of the treatment response, while the PKPD model uses the data also to further the individualisation of predictions.

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.

Dataset Information

Continuous Learning in Model-Informed Precision Dosing: A Case Study in Pediatric Dosing of Vancomycin.

Publications

Continuous Learning in Model-Informed Precision Dosing: A Case Study in Pediatric Dosing of Vancomycin.

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