Clinical Pharmacokinetics

, Volume 56, Issue 4, pp 435–447 | Cite as

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

  • Michaël PhilippeEmail author
  • Michael Neely
  • Yves Bertrand
  • Nathalie Bleyzac
  • Sylvain Goutelle
Original Research Article


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.


Therapeutic Drug Monitoring Busulfan Target Interval Dose Individualization Busulfan Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards


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.

Supplementary material

40262_2016_448_MOESM1_ESM.docx (40 kb)
Supplementary material 1 (DOCX 40 kb)


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Michaël Philippe
    • 1
    • 2
    Email author
  • Michael Neely
    • 3
  • Yves Bertrand
    • 1
  • Nathalie Bleyzac
    • 1
    • 2
  • Sylvain Goutelle
    • 2
    • 4
    • 5
  1. 1.Institute of Pediatric Hematology and Oncology, Place Professeur Joseph RenautLyonFrance
  2. 2.Laboratoire de Biométrie et Biologie EvolutiveUMR CNRS 5558, Université Lyon 1VilleurbanneFrance
  3. 3.Laboratory of Applied Pharmacokinetics and Bioinformatics, Division of Pediatric Infectious DiseasesUniversity of Southern California Children’s Hospital Los AngelesLos AngelesUSA
  4. 4.ISPB-Faculté de Pharmacie de LyonUniversité Lyon 1LyonFrance
  5. 5.Service PharmaceutiqueGroupement Hospitalier de Gériatrie, Hospices Civils de LyonLyonFrance

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