caa a22 4500 605534047 CHVBK 20210128100841.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s10928-015-9419-z doi (NATIONALLICENCE)springer-10.1007/s10928-015-9419-z Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model [Elektronische Daten] [Michael Lyons, Anne Lenaerts] One critical approach to preclinical evaluation of anti-tuberculosis (anti-TB) drugs is the study of correlations between drug exposure and efficacy in animal TB infection models. While such pharmacokinetic/pharmacodynamic (PK/PD) studies are useful for the identification of optimal clinical dosing regimens, they are resource intensive and are not routinely performed. A mathematical model capable of simulating the PK/PD properties of drug therapy for experimental TB offers a way to mitigate some of the practical obstacles to determining the PK/PD index that best correlates with efficacy. Here, we present a preliminary physiologically based PK/PD model of rifampin therapy in a mouse TB infection model. The computational framework integrates whole-body rifampin PKs, cell population dynamics for the host immune response to Mycobacterium tuberculosis infection, drug-bacteria interactions, and a Bayesian method for parameter estimation. As an initial application, we calibrated the model to a set of available rifampin PK/PD data and simulated a separate dose fractionation experiment for bacterial killing kinetics in the lungs of TB-infected mice. The simulation results qualitatively agreed with the experimentally observed PK/PD correlations, including the identification of area under the concentration-time curve as best correlating with efficacy. This single-drug framework is aimed toward extension to multiple anti-TB drugs in order to facilitate development of optimal combination regimens. Springer Science+Business Media New York, 2015 Rifampin nationallicence PKPD nationallicence Tuberculosis nationallicence Mice nationallicence Immune response nationallicence Modeling nationallicence Lyons Michael Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA aut Lenaerts Anne Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 375-389 1567-567X 42:4<375 2015 42 10928 https://doi.org/10.1007/s10928-015-9419-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9419-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lyons Michael Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA aut NATIONALLICENCE 700 1- Lenaerts Anne Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 375-389 1567-567X 42:4<375 2015 42 10928