Optimizing study design in LPS challenge studies for quantifying drug induced inhibition of TNFα response: Did we miss the prime time?

European Journal of Pharmaceutical Sciences, vol. 176, pp. 106256

Abstract

In this work we evaluate the study design of LPS challenge experiments used for quantification of drug induced inhibition of TNFα response and provide general guidelines of how to improve the study design. Analysis of model simulated data, using a recently published TNFα turnover model, as well as the optimal design tool PopED have been used to find the optimal values of three key study design variables - time delay between drug and LPS administration, LPS dose, and sampling time points - that in turn could make the resulting TNFα response data more informative. Our findings suggest that the current rule of thumb for choosing the time delay should be reconsidered, and that the placement of the measurements after maximal TNFα response are crucial for the quality of the experiment. Furthermore, a literature study summarizing a wide range of published LPS challenge studies is provided, giving a broader perspective of how LPS challenge studies are usually conducted both in a preclinical and clinical setting.

Authors 5

1. Julia Larsson corresponding

   Fraunhofer Chalmers Research Centre for Industrial Mathematics · Chalmers University of Technology · University of Gothenburg

   Affiliation as printed

   Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg 412 88, Sweden; Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg 412 96, Sweden. Electronic address: julia.larsson@fcc.chalmers.se

   Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg 412 96, Sweden

   Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg 412 88, Sweden

2. Edmund Hoppe Aachen Grünenthal GmbH

   Grünenthal Group (Germany)

   Affiliation as printed

   Grünenthal GmbH, Aachen, Germany

3. Michael Gautrois Aachen Grünenthal GmbH

   Grünenthal Group (Germany)

   Affiliation as printed

   Grünenthal GmbH, Aachen, Germany

4. Marija Cvijović

   Chalmers University of Technology · University of Gothenburg

   Affiliation as printed

   Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg 412 96, Sweden

5. Mats Jirstrand

   Fraunhofer Chalmers Research Centre for Industrial Mathematics

   Affiliation as printed

   Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg 412 88, Sweden