Optimizing study design in LPS challenge studies for quantifying drug induced inhibition of TNFα response: Did we miss the prime time?
Journal article, 2022

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.


Tumor necrosis factor alpha

Pharmacokinetics and pharmacodynamics

Optimal design

Non-linear mixed effects modeling


Julia Larsson

University of Gothenburg

Fraunhofer-Chalmers Centre

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Edmund Hoppe

Grünenthal GmbH

Michael Gautrois

Grünenthal GmbH

Marija Cvijovic

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

University of Gothenburg

Mats Jirstrand

Fraunhofer-Chalmers Centre

European Journal of Pharmaceutical Sciences

0928-0987 (ISSN)

Vol. 176 106256

Subject Categories

Pharmaceutical Sciences

Medical Laboratory and Measurements Technologies

Other Engineering and Technologies not elsewhere specified





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8/3/2022 9