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Tuberculosis pharmacokinetics

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https://www.readbyqxmd.com/read/28817561/comparing-efficacies-of-moxifloxacin-levofloxacin-and-gatifloxacin-in-tuberculosis-granulomas-using-a-multi-scale-systems-pharmacology-approach
#1
Elsje Pienaar, Jansy Sarathy, Brendan Prideaux, Jillian Dietzold, Véronique Dartois, Denise E Kirschner, Jennifer J Linderman
Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data are available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. To predict the efficacy of MXF, LVX and GFX at a single granuloma level, we integrate computational modeling with experimental datasets into a single mechanistic framework, GranSim...
August 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28807911/systematic-review-and-meta-analyses-of-the-effect-of-chemotherapy-on-pulmonary-mycobacterium-abscessus-outcomes-and-disease-recurrence
#2
Jotam G Pasipanodya, Deborah Ogbonna, Beatriz E Ferro, Gesham Magombedze, Shashikant Srivastava, Devyani Deshpande, Tawanda Gumbo
Background. In pharmacokinetic/pharmacodynamics models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown.Methods We searched the literature for studies published between 1990-2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. Good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28803492/rifampin-vs-rifapentine-what-is-the-preferred-rifamycin-for-tuberculosis
#3
Omamah Alfarisi, Wael A Alghamdi, Mohammad H Al-Shaer, Kelly E Dooley, Charles A Peloquin
One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis treatment? Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics (PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for comparing them...
August 14, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28799307/guiding-principles-for-the-use-of-fluroquinolones-in-out-patient-community-settings-of-india-panel-consensus
#4
Agam Vora, K Krishnaprasad
INTRODUCTION: Respiratory tract infections have been an important cause of morbidity and mortality worldwide that is looming large especially in context of antibiotic resistance that is confronted both by a pulmonologist as well as a general practitioner. A reflection to this trend has been the rising phenomenon of MICs as shown the respiratory pathogens towards conventional antibiotics including macrolides or β lactam/β lactamase inhibitor combinations. Respiratory fluoroquinolones offer broad yet potent cover of respiratory pathogens leading to their obvious choice for empirical therapy for clinical persisters or high risk cases with prior history of antibiotics not-withstanding the clinical concerns in tropical countries...
August 2017: Journal of the Association of Physicians of India
https://www.readbyqxmd.com/read/28789609/dose-and-time-dependency-of-the-toxicity-and-pharmacokinetic-profiles-of-bedaquiline-and-its-n-desmethyl-metabolite-in-dogs
#5
Ilham Smyej, Sandra De Jonghe, Adriana Looszova, Geert Mannens, Tom Verhaeghe, Sandy Thijssen, Sofie Starckx, Ann Lampo, Marie-Claude Rouan
Bedaquiline (BDQ) is an antibiotic to treat pulmonary multidrug-resistant tuberculosis (MDR-TB). Studies up to 39 weeks were conducted orally in dogs to assess the toxicity and pharmacokinetics of BDQ and its N-desmethyl metabolite (D-BDQ). Phospholipidosis (PLD) seen in the monocytic phagocytic system was considered an adaptive change. Skeletal muscle, heart, stomach, liver, and pancreas toxicities with D-BDQ as the main contributor were associated with a less-than-dose-proportional increase in plasma exposure and an overproportional tissue uptake of BDQ and D-BDQ at high-dose levels...
January 1, 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28741299/a-review-of-moxifloxacin-for-the-treatment-of-drug-susceptible-tuberculosis
#6
REVIEW
Anushka Naidoo, Kogieleum Naidoo, Helen McIlleron, Sabiha Essack, Nesri Padayatchi
Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance...
July 24, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28739794/population-pharmacokinetics-of-azd-5847-in-adults-with-pulmonary-tuberculosis
#7
Abdullah Alsultan, Jennifer J Furin, Jeannine Du Bois, Elana van Brakel, Phalkun Chheng, Amour Venter, Bonnie Thiel, Sara A Debanne, W Henry Boom, Andreas H Diacon, John L Johnson, Charles A Peloquin
AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis. In this study we describe the population pharmacokinetics of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug susceptible TB. Patients were randomized to four doses (500 mg once daily, 1200 mg once daily, 500 mg twice daily and 800 mg twice daily). Patients were intensively sampled on day 1 and 14. AZD-5847 pharmacokinetics were best described with a two compartment system with tlag for absorption...
July 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28739783/effect-of-rifampin-on-the-single-dose-pharmacokinetics-of-oral-cabotegravir-in-healthy-subjects
#8
S L Ford, K Sutton, Y Lou, Z Zhang, A Tenorio, C Trezza, P Patel, W Spreen
Introduction: Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection.Methods: This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir...
July 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28715978/the-role-of-efflux-pumps-in-tuberculosis-treatment-and-their-promise-as-a-target-in-drug-development-unraveling-the-black-box
#9
Lindsey H M Te Brake, Gerjo J de Knegt, Jurriaan E de Steenwinkel, Teunis J P van Dam, David M Burger, Frans G M Russel, Reinout van Crevel, Jan B Koenderink, Rob E Aarnoutse
Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs systemically and locally. Firstly, transporters located in the intestines, liver, and kidneys all determine the pharmacokinetics and pharmacodynamics of anti-TB drugs, with a high risk of drug-drug interactions in the setting of concurrent use of antimycobacterial, antiretroviral, and antidiabetic agents...
July 17, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28696241/ethambutol-partitioning-in-tuberculous-pulmonary-lesions-explains-its-clinical-efficacy
#10
Matthew Zimmerman, Jodi Lestner, Brendan Prideaux, Paul O'Brien, Isabela Freedman, Chao Chen, Jillian Dietzold, Isaac Daudelin, Firat Kaya, Landry Blanc, Pei-Yu Chen, Steven Park, Padmini Salgame, Jansy Sarathy, Véronique Dartois
Clinical trials and practice have shown that ethambutol is an important component of the first line tuberculosis (TB) regime. This contrasts the drug's rather modest potency and lack of activity against non-growing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile of ethambutol suggests that the drug may be of limited clinical value. Here we hypothesized that this apparent contradiction may be explained by favorable penetration of the drug into TB lesions. First we utilized novel in vitro lesion pharmacokinetic assays and predicted good penetration of the drug into lesions...
July 10, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28657202/assessing-pharmacodynamic-interactions-in-mice-using-the-multistate-tuberculosis-pharmacometric-and-general-pharmacodynamic-interaction-models
#11
Chunli Chen, Sebastian G Wicha, Gerjo J de Knegt, Fatima Ortega, Laura Alameda, Veronica Sousa, Jurriaan E M de Steenwinkel, Ulrika S H Simonsson
The aim of this study was to investigate pharmacodynamic interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics, 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 pharmacodynamic interactions were observed against fast-multiplying bacteria...
June 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28653479/a-population-pharmacokinetic-model-incorporating-saturable-pharmacokinetics-and-autoinduction-for-high-rifampicin-doses
#12
Robin J Svensson, Rob E Aarnoutse, Andreas H Diacon, Rodney Dawson, Stephen H Gillespie, Martin J Boeree, Ulrika S H Simonsson
Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling...
June 27, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28643624/preclinical-efficacy-testing-of-new-drug-candidates
#13
Eric L Nuermberger
This is a review of the preclinical efficacy testing of new antituberculosis drug candidates. It describes existing dynamic in vitro and in vivo models of antituberculosis chemotherapy and their utility in preclinical evaluations of promising new drugs and combination regimens, with an effort to highlight recent developments. Emphasis is given to the integration of quantitative pharmacokinetic/pharmacodynamic analyses and the impact of lesion pathology on drug efficacy. Discussion also includes in vivo models of chemotherapy of latent tuberculosis infection...
June 2017: Microbiology Spectrum
https://www.readbyqxmd.com/read/28626525/identification-of-better-pharmacokinetic-benzothiazinone-derivatives-as-new-antitubercular-agents
#14
Kai Lv, Xuefu You, Bin Wang, Zengquan Wei, Yun Chai, Bo Wang, Apeng Wang, Guocheng Huang, Mingliang Liu, Yu Lu
A series of new 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one(BTZ) derivatives containing a C-2 nitrogen spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent in vitro activity (MIC < 0.15 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains. Compounds 11l and 11m display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28623772/development-and-validation-of-a-highly-sensitive-lc-esi-ms-ms-method-for-estimation-of-iiim-mcd-211-a-novel-nitrofuranyl-methyl-piperazine-derivative-with-potential-activity-against-tuberculosis-application-to-drug-development
#15
Asmita Magotra, Anjna Sharma, Ajai Prakash Gupta, Priya Wazir, Shweta Sharma, Parvinder Pal Singh, Manoj Kumar Tikoo, Ram A Vishwakarma, Gurdarshan Singh, Utpal Nandi
In the present study, a simple, sensitive, specific and rapid liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was developed and validated according to the Food and Drug Administration (FDA) guidelines for estimation of IIIM-MCD-211 (a potent oral candidate with promising action against tuberculosis) in mice plasma using carbamazepine as internal standard (IS). Bioanalytical method consisted of one step protein precipitation for sample preparation followed by quantitation in LC-MS/MS using positive electrospray ionization technique (ESI) operating in multiple reaction monitoring (MRM) mode...
June 8, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28609019/synthesis-biological-evaluation-and-molecular-docking-studies-of-novel-3-aryl-5-alkyl-thio-1h-1-2-4-triazoles-derivatives-targeting-mycobacterium-tuberculosis
#16
Navnath D Rode, Amol D Sonawane, Laxman Nawale, Vijay M Khedkar, Ramesh A Joshi, Anjali P Likhite, Dhiman Sarkar, Rohini R Joshi
A small library of new 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles was synthesized and screened for the anti-mycobacterial potency against M. tuberculosis H37 Ra strain and M. bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti-TB activity in the range of IC50 0.03-5.88 μg/mL for dormant stage and 20 compounds in the range of 0.03-6.96 μg/mL for active stage. Their lower toxicity (>100 μg/mL) and higher selectivity (SI = >10) against all cancer cell lines screened makes them interesting compounds with potential anti-mycobacterial effects...
June 13, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28607022/pharmacokinetics-of-pyrazinamide-and-optimal-dosing-regimens-for-drug-sensitive-and-resistant-tuberculosis
#17
Maxwell T Chirehwa, Helen McIlleron, Roxana Rustomjee, Thuli Mthiyane, Philip Onyebujoh, Peter Smith, Paolo Denti
Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB)...
August 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28584143/linezolid-dose-that-maximizes-sterilizing-effect-while-minimizing-toxicity-and-resistance-emergence-for-tuberculosis
#18
Shashikant Srivastava, Gesham Magombedze, Thearith Koeuth, Carleton Sherman, Jotam G Pasipanodya, Prithvi Raj, Edward Wakeland, Devyani Deshpande, Tawanda Gumbo
Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months...
August 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28561946/new-paradigm-for-translational-modeling-to-predict-long-term-tuberculosis-treatment-response
#19
I H Bartelink, N Zhang, R J Keizer, N Strydom, P J Converse, K E Dooley, E L Nuermberger, R M Savic
Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology...
May 31, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28559269/pharmacokinetic-evidence-from-the-hirif-trial-to-support-increased-doses-of-rifampin-for-tuberculosis
#20
C A Peloquin, G E Velásquez, L Lecca, R I Calderón, J Coit, M Milstein, E Osso, J Jimenez, K Tintaya, E Sanchez Garavito, D Vargas Vasquez, C D Mitnick, G Davies
Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30...
August 2017: Antimicrobial Agents and Chemotherapy
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