Open AccessAssessing Pharmacodynamic Interactions in Mice Using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models
Author(s) -
Chen Chunli,
Wicha Sebastian G.,
de Knegt Gerjo J.,
Ortega Fatima,
Alameda Laura,
Sousa Veronica,
de Steenwinkel Jurriaan E. M.,
Simonsson Ulrika S. H.
Publication year - 2017
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12226
Subject(s) - ethambutol , pyrazinamide , rifampicin , isoniazid , pharmacodynamics , pharmacology , mycobacterium tuberculosis , tuberculosis , medicine , population , pharmacokinetics , drug interaction , pathology , environmental health
The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast‐multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non‐multiplying bacteria were identified, which led to an increase of 0.86 log 10 colony‐forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non‐multiplying bacteria was quantified, which led to a decrease of 2.84 log 10 CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development.