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Assessing Pharmacod...
Assessing Pharmacodynamic Interactions in Mice using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models
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- Chen, Chunli (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Northeast Agr Univ, Coll Vet Med, 600 Changjiang Rd, Harbin 150030, Heilongjiang, Peoples R China. Heilongjiang Key Lab Anim Dis Control & Pharmaceu, 600 Changjiang Rd, Harbin 150030, Heilongjiang, Peoples R China.
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- Wicha, Sebastian G. (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- de Knegt, Gerjo (författare)
- Erasmus MC, Department of Medical Microbiology and Infectious Disease, University Medical Centre Rotterdam, Rotterdam, the Netherlands
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- Ortega, Fatima (författare)
- Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain
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- Alameda, Laura (författare)
- Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain
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- Veronica, Sousa (författare)
- Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain
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- de Steenwinkel, Jurriaan (författare)
- Erasmus MC, Department of Medical Microbiology and Infectious Disease, University Medical Centre Rotterdam, Rotterdam, the Netherlands
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- Simonsson, Ulrika S H, Professor (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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(creator_code:org_t)
- 2017-10-10
- 2017
- Engelska.
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Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 6:11, s. 787-797
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- tuberculosis
- pharmacokinetics-pharmacodynamics
- drug-drug interactions
- mixed effect models
- pharmacometrics
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