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Robust Population Pharmacokinetic Experiment Design

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The population approach to estimating mixed effects model parameters of interest in pharmacokinetic (PK) studies has been demonstrated to be an effective method in quantifying relevant population drug properties. The information available for each individual is usually sparse. As such, care should be taken to ensure that the information gained from each population experiment is as efficient as possible by designing the experiment optimally, according to some criterion. The classic approach to this problem is to design “good” sampling schedules, usually addressed by the D-optimality criterion. This method has the drawback of requiring exact advanced knowledge (expected values) of the parameters of interest. Often, this information is not available. Additionally, if such prior knowledge about the parameters is misspecified, this approach yields designs that may not be robust for parameter estimation. In order to incorporate uncertainty in the prior parameter specification, a number of criteria have been suggested. We focus on ED-optimality. This criterion leads to a difficult numerical problem, which is made tractable here by a novel approximation of the expectation integral usually solved by stochastic integration techniques. We present two case studies as evidence of the robustness of ED-optimal designs in the face of misspecified prior information. Estimates from replicate simulated population data show that such misspecified ED-optimal designs recover parameter estimates that are better than similarly misspecified D-optimal designs, and approach estimates gained from D-optimal designs where the parameters are correctly specified.

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Authors and Affiliations

  1. Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, Box 352255, Seattle, 98195-2255, WA, USA

    Michael G. Dodds, Andrew C. Hooker & Paolo Vicini

  2. Pre-Clinical Development, ZymoGenetics, Inc, 1201 Eastlake Avenue, Seattle, 98102, WA, USA

    Michael G. Dodds

  3. Division of Pharmacokinetics and Drug Therapy, Uppsala University, Biomedical Centre, Box 591, Uppsala, 751 24, SE, Sweden

    Andrew C. Hooker

Authors
  1. Michael G. Dodds
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  2. Andrew C. Hooker
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  3. Paolo Vicini
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Correspondence to Paolo Vicini.

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Dodds, M.G., Hooker, A.C. & Vicini, P. Robust Population Pharmacokinetic Experiment Design. J Pharmacokinet Pharmacodyn 32, 33–64 (2005). https://doi.org/10.1007/s10928-005-2102-z

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