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A Nonparametric Method to Optimize Initial Drug Dosing and Attainment of a Target Exposure Interval: Concepts and Application to Busulfan in Pediatrics

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Abstract

The traditional approach for model-based initial dosing is based on the use of a single vector of typical population parameters for targeting a specific exposure. This approach is theoretically ill-suited for targeting a range of exposure. The objective of this work was to develop a general approach for optimal (OPT) targeting of a drug exposure interval. After methodological purposes, we applied our method to the busulfan case. We used a nonparametric population pharmacokinetic model of intravenous busulfan to estimate the individual pharmacokinetic parameters of 163 bone marrow-transplanted children. Then, an array of 151 doses of busulfan ranging from 0.5 to 2 mg/kg was simulated a priori in each patient. For each dose, 29 possible busulfan plasma concentration profiles, corresponding to the nonparametric prior, each associated with a probability, were obtained. The multiple-model-based, OPT dose was identified as the dose maximizing the a priori probability of achieving the busulfan target area under the concentration-time curve (AUC). Two AUC targets were considered: 900–1500 (conventional) or <1500 µM min−1. Finally, the OPT dose was individually simulated in each patient. We compared the ability of this method to achieve the target exposure interval with that of three other traditional model-based methods and one based on the non-parametric approach. When targeting the busulfan conventional AUC range, the OPT dose provided better attainment than the best of the three other methods after one dose (82.2 vs. 41.7 %, p < 0.005), two doses (79.1 vs. 65.0 %, p < 0.005), and at the end of therapy (80.4 vs. 76.7 %, p < 0.42). The approach provided a balanced distribution between under- (10.4 %) and overexposure (9.2 %), while other approaches showed higher rates of underexposure (≥19 %). When targeting an AUC <1500 µM min, the OPT dose was successful in minimizing overexposure as 0 % of children showed simulated AUC >1500 µM min−1. Our approach has been designed to optimize the targeting of an exposure interval. When applied to busulfan in children, it outperformed the traditional model-based dosing approach, with earlier and better achievement of busulfan target AUC. The approach can be applied for OPT dosing of many drugs, when the target objective is an interval.

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Authors and Affiliations

  1. Institute of Pediatric Hematology and Oncology, Place Professeur Joseph Renaut, 69008, Lyon, France

    Michaël Philippe, Yves Bertrand & Nathalie Bleyzac

  2. Laboratoire de Biométrie et Biologie Evolutive, UMR CNRS 5558, Université Lyon 1, Villeurbanne, France

    Michaël Philippe, Nathalie Bleyzac & Sylvain Goutelle

  3. Laboratory of Applied Pharmacokinetics and Bioinformatics, Division of Pediatric Infectious Diseases, University of Southern California Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Michael Neely

  4. ISPB-Faculté de Pharmacie de Lyon, Université Lyon 1, Lyon, France

    Sylvain Goutelle

  5. Service Pharmaceutique, Groupement Hospitalier de Gériatrie, Hospices Civils de Lyon, Lyon, France

    Sylvain Goutelle

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  1. Michaël Philippe
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Correspondence to Michaël Philippe.

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Funding

No sources of funding were used for this work. This work was not supported by any academic, company, or sponsor funds.

Conflict of interest

Michael Philippe, Yves Bertrand, Nathalie Bleyzac, and Sylvain Goutelle declare that they have no conflicts of interest. Michael Neely is partly supported by NIH-NIGMS R01 GM068968 and NIH-NICHD R01 HD070886.

Ethical approval

This was a non-interventional study without any additional procedure than those used in routine patient care. For these reasons, no institutional review board or ethics committee approval was required, in accordance with the French regulation on biomedical research.

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Philippe, M., Neely, M., Bertrand, Y. et al. A Nonparametric Method to Optimize Initial Drug Dosing and Attainment of a Target Exposure Interval: Concepts and Application to Busulfan in Pediatrics. Clin Pharmacokinet 56, 435–447 (2017). https://doi.org/10.1007/s40262-016-0448-6

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