title: The multistate tuberculosis pharmacometric model: a semi-mechanistic pharmacokinetic-pharmacodynamic model for studying drug effects in an acute tuberculosis mouse model.
abstract: The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98 mg·kg-1·day-1; Days 1-8; 5 each dose level) and were sacrificed on Day 9. Twenty mice received oral rifampicin (30 mg·kg-1·day-1; up to 8 days) and were sacrificed on Days 2, 3, 4 and 9 (5 each day). The MTP model was linked to a rifampicin population pharmacokinetic model to describe the change in colony forming units (CFU) in the lungs over time. The transfer rates between the different bacterial states were fixed to estimates from in vitro data. The MTP model described well the change in CFU over time after different exposure levels of rifampicin in an acute tuberculosis mouse model. Rifampicin significantly inhibited the growth of fast-multiplying bacteria and stimulated the death of fast- and slow-multiplying bacteria. The data did not support an effect of rifampicin on non-multiplying bacteria possibly due to the short duration of the study. The pharmacometric modelling framework using the MTP model can be used to perform investigations and predictions of the efficacy of anti-tubercular drugs against different bacterial states.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden. chunli.chen@farmbio.uu.se.
authors.forename: Chunli
authors.initials: C
authors.lastname: Chen
authors.affiliation: Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Rullas
authors.affiliation: Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Alameda
authors.affiliation: Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.|The Art of Discovery (TAD), Biscay Science and Technology Park, Astondo Bidea, BIC Bizkaia building, No.612, 48160, Derio, Bizkaia, Basque Country, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden.
authors.forename: Ulrika Sh
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin
keywords: Mouse; Pharmacodynamics; Pharmacokinetics; Rifampicin; Tuberculosis