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pharmacokinetics and TB

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https://www.readbyqxmd.com/read/29145924/pharmacokinetic-interaction-between-bedaquiline-and-clofazimine-in-patients-with-drug-resistant-tuberculosis
#1
G Maartens, M J E Brill, M Pandie, E M Svensson
<h2>BACKGROUND:</h2>Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.<h2>METHODS:</h2>We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB...
November 16, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29133560/levofloxacin-population-pharmacokinetics-in-south-african-children-treated-for-multidrug-resistant-tuberculosis
#2
Paolo Denti, Anthony J Garcia-Prats, Heather R Draper, Lubbe Wiesner, Jana Winckler, Stephanie Thee, Kelly E Dooley, Rada M Savic, Helen M McIlleron, H Simon Schaaf, Anneke C Hesseling
Background: Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited paediatric pharmacokinetic data to inform dose selection for children.Methods: Children routinely receiving levofloxacin (250 mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following a 15 or 20 mg/kg dose, given as whole tablet(s) or crushed, orally, or by nasogastric tube. Pharmacokinetic parameters were estimated using non-linear mixed effects modelling...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29133558/pharmacokinetics-and-drug-drug-interactions-of-lopinavir-ritonavir-administered-with-first-and-second-line-antituberculosis-drugs-in-hiv-infected-children-treated-for-multidrug-resistant-tuberculosis
#3
Louvina E van der Laan, Anthony J Garcia-Prats, H Simon Schaaf, Tjokosela Tikiso, Lubbe Wiesner, Mine de Kock, Jana Winckler, Jennifer Norman, Helen McIlleron, Paolo Denti, Anneke C Hesseling
Background Lopinavir/ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir/ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir/ritonavir and routine drugs used for MDR-TB treatment in HIV-infected children.Methods A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 on MDR-TB treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin: and 16 without TB), who were established on a lopinavir/ritonavir-containing antiretroviral regimen...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29066867/clinical-and-pharmacological-hallmarks-of-rifapentine-s-use-in-diabetes-patients-with-active-and-latent-tuberculosis-do-we-know-enough
#4
REVIEW
Chunlan Zheng, Xiufen Hu, Li Zhao, Minhui Hu, Feng Gao
Rifapentine is a rifamycin derivate approved by the US Food and Drug Administration in 1998 for the treatment of active, drug-susceptible tuberculosis (TB). In 2014, rifapentine was approved for the treatment of latent TB infection in patients at high risk of progression to active disease and is currently under evaluation by the European Medicines Agency. Expanding indications of rifapentine largely affect diabetes patients, since about one-third of them harbor latent TB. Clinical consequences of rifapentine use in this population and potentially harmful interactions with hypoglycemic agents are widely underexplored and generally considered similar to the ones of rifampicin...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29061739/impact-of-rifabutin-or-rifampin-on-bedaquiline-safety-tolerability-and-pharmacokinetics-a-randomized-clinical-trial-in-healthy-adult-volunteers
#5
Amanda M Healan, J McLeod Griffiss, Howard M Proskin, Mary Ann O'Riordan, Wesley A Gray, Robert A Salata, Jeffrey L Blumer
Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial adenosine triphosphate synthase. Bedaquiline has effectively treated disease caused by susceptible and drug-resistant Mycobacterium tuberculosis (TB). Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This Phase 1, open label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose...
October 23, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29050764/pharmacokinetic-studies-of-a-three-component-complex-that-repurposes-the-front-line-antibiotic-isoniazid-against-mycobacterium-tuberculosis
#6
Thomas J Manning, Kyle Wilkerson, Taylor Holder, Andrew Carson Bartley, Chelsea Jackson, Sydney Plummer, Dennis Phillips, Logan Krajewski, Greg Wylie
The frontline tuberculosis (Tb) antibiotic isoniazid has been repurposed using a three component complex aimed at increasing the delivery efficiency and adding new avenues to its mechanism of action. This study focuses on pharmacokinetic studies of the isoniazid-sucrose-copper (II)-PEG-3350 complex. The assays include the Plasma Protein Binding Assay (85.8%), Caco-2 Permeability Assay (B→APapp, 0.13 × 10(-6) cm/s), Cytochrome P450 Inhibition Assay (i.e. CYP2B6, IC50 = 7.26 μM), In vitro microsomal Stability Assay (t1/2 NADPH-Dependent > 240 min), and HepG2 Cytotoxicity (no toxicity)...
December 2017: Tuberculosis
https://www.readbyqxmd.com/read/29038231/evaluation-of-clinical-drug-interaction-potential-of-clofazimine-using-static-and-dynamic-modeling-approaches
#7
Ramachandra Sangana, Helen Gu, Dung Yu Chun, Heidi J Einolf
The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (CYP) inhibitor in vitro, a CYP-mediated drug interaction may be likely when clofazimine is co-administered with substrates of these enzymes. The CYP-mediated drug interaction potential of clofazimine was evaluated using both static (estimation of "R1" and area under the plasma concentration-time curve ratio [AUCR] values) and dynamic (physiologically based pharmacokinetic [PBPK]) modeling approaches...
October 16, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29037995/preclinical-pharmacokinetic-profiling-of-iqg-607-a-potential-oral-metallodrug-to-treat-tuberculosis
#8
Adilio da S Dadda, Valnês S Rodrigues-Junior, Fernando Carreño, Guilherme O Petersen, Antônio F M Pinto, Pedro F Dalberto, Nathalia D M Sperotto, Kenia Pissinate, Cristiano V Bizarro, Pablo Machado, Maria M Campos, Teresa Dalla Costa, Diógenes S Santos, Luiz A Basso
IQG-607 is an analog of isoniazid with anti-tuberculosis activity. This work describes the development and validation of an HPLC method to quantify pentacyano(isoniazid)ferrate(II) compound (IQG-607) and the pharmacokinetic studies of this compound in mice. The method showed linearity in the 0.5-50μg/mL concentration range (r=0.9992). Intra- and inter-day precision was <5%, and the recovery ranged from 92.07 to 107.68%. IQG-607 was stable in plasma for at least 30days at -80°C and, after plasma processing, for 4h in the auto-sampler maintained on ice (recovery >85%)...
October 14, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29023399/novel-anti-tuberculosis-nanodelivery-formulation-of-ethambutol-with-graphene-oxide
#9
Bullo Saifullah, Alina Chrzastek, Arundhati Maitra, Bullo Naeemullah, Sharida Fakurazi, Sanjib Bhakta, Mohd Zobir Hussein
Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients' noncompliance due to dosing frequency, lengthy treatment, and adverse side effects associated with current chemotherapy. However, no modifications to the half-a-century old standard chemotherapy have been made based on a nanoformulation strategy to improve pharmacokinetic efficacy. In this study, we have designed a new nanodelivery formulation, using graphene oxide as the nanocarrier, loaded with the anti-TB antibiotic, ethambutol...
October 12, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28993169/anti-tuberculosis-drug-combination-for-controlled-oral-delivery-using-3d-printed-compartmental-dosage-forms-from-drug-product-design-to-in-vivo-testing
#10
Natalja Genina, Johan Peter Boetker, Stefano Colombo, Necati Harmankaya, Jukka Rantanen, Adam Bohr
The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments...
October 6, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28961790/modelling-of-mycobacterial-load-reveals-bedaquiline-s-exposure-response-relationship-in-patients-with-drug-resistant-tb
#11
Elin M Svensson, Mats O Karlsson
Background: Bedaquiline has been shown to reduce time to sputum culture conversion (SCC) and increase cure rates in patients with drug-resistant TB, but the influence of drug exposure remains uncharacterized. Objectives: To investigate whether an exposure-response relationship could be characterized by making better use of the existing information on pharmacokinetics and longitudinal measurements of mycobacterial load. Methods: Quantitative culture data in the form of time to positivity (TTP) in mycobacterial growth indicator tubes obtained from a randomized placebo-controlled Phase IIb registration trial were examined using non-linear mixed-effects methodology...
September 13, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28953378/discovery-of-a-potent-and-specific-m-tuberculosis-leucyl-trna-synthetase-inhibitor-s-3-aminomethyl-4-chloro-7-2-hydroxyethoxy-benzo-c-1-2-oxaborol-1-3h-ol-gsk656
#12
Xianfeng Li, Vincent Hernandez, Fernando L Rock, Wai Choi, Yvonne S L Mak, Manisha Mohan, Weimin Mao, Yasheen Zhou, Eric E Easom, Jacob J Plattner, Wuxin Zou, Esther Pérez-Herrán, Ilaria Giordano, Alfonso Mendoza-Losana, Carlos Alemparte, Joaquín Rullas, Iñigo Angulo-Barturen, Sabrinia Crouch, Fátima Ortega, David Barros, M R K Alley
There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656)...
October 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28928173/cohort-profile-of-a-study-on-outcomes-related-to-tuberculosis-and-antiretroviral-drug-concentrations-in-uganda-design-methods-and-patient-characteristics-of-the-south-study
#13
Christine Sekaggya-Wiltshire, Barbara Castelnuovo, Amrei von Braun, Joseph Musaazi, Daniel Muller, Allan Buzibye, Ursula Gutteck, Lars Henning, Bruno Ledergerber, Natascia Corti, Mohammed Lamorde, Jan Fehr, Andrew Kambugu
PURPOSE: Tuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes. PARTICIPANTS: Patients diagnosed with new pulmonary TB at the integrated TB-HIV outpatient clinic in Kampala, Uganda, were enrolled into the study and started on first-line anti-TB treatment...
September 18, 2017: BMJ Open
https://www.readbyqxmd.com/read/28862186/food-significantly-reduces-plasma-concentrations-of-first-line-anti-tuberculosis-drugs
#14
Agibothu Kupparam Hemanth Kumar, Vedachalam Chandrasekaran, Angadi Kiran Kumar, M Kawaskar, J Lavanya, Soumya Swaminathan, Geetha Ramachandran
BACKGROUND & OBJECTIVES: Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug concentrations. This study was undertaken to examine the effect of food on two-hour plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA), and pharmacokinetics of these drugs in adult TB patients. METHODS: Newly diagnosed adult TB patients were recruited from the Revised National Tuberculosis Control Programme (RNTCP) treatment centres in Chennai Corporation, Chennai, India...
April 2017: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/28861054/screening-of-tb-actives-for-activity-against-nontuberculous-mycobacteria-delivers-high-hit-rates
#15
Jian Liang Low, Mu-Lu Wu, Dinah Binte Aziz, Benoît Laleu, Thomas Dick
The prevalence of lung disease due to infections with nontuberculous mycobacteria (NTM) has been increasing and surpassed tuberculosis (TB) in some countries. Treatment outcomes are often unsatisfactory, highlighting an urgent need for new anti-NTM medications. Although NTM in general do not respond well to TB specific drugs, the similarities between NTM and Mycobacterium tuberculosis at the molecular and cell structural level suggest that compound libraries active against TB could be leveraged for NTM drug discovery...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28859520/the-downfall-of-tba-354-a-possible-explanation-for-its-neurotoxicity-via-mass-spectrometric-imaging
#16
Sphamandla Ntshangase, Adeola Shobo, Hendrik G Kruger, Arndt Asperger, Dagmar Niemeyer, Per I Arvidsson, Thavendran Govender, Sooraj Baijnath
TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LC-MS/MS) and mass spectrometric imaging (MSI), respectively...
September 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28843937/determination-of-protein-unbound-active-rifampicin-in-serum-by-ultrafiltration-and-ultra-performance-liquid-chromatography-with-uv-detection-a-method-suitable-for-standard-and-high-doses-of-rifampicin
#17
Eleonora W J van Ewijk-Beneken Kolmer, Marga J A Teulen, Erik C A van den Hombergh, Nielka E van Erp, Lindsey H M Te Brake, Rob E Aarnoutse
Rifampicin is the most important antibiotic in use for the treatment of tuberculosis (TB). Preclinical and clinical data suggest that higher doses of rifampicin, resulting in disproportionally higher systemic exposures to the drug, are more effective. Serum concentrations of rifampicin are the intermediary link between the dose administered and eventual response and only protein-unbound (free) rifampicin is pharmacologically active. The objective of this work was to develop an ultra performance liquid chromatography assay for protein-unbound rifampicin in serum with ultrafiltration, carried out at a sample temperature of 37°C, suitable for measurement of concentrations achieved after currently used and higher doses of rifampicin...
September 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28827417/pharmacokinetics-tolerability-and-bacteriological-response-of-rifampin-administered-at-600-900-and-1-200-milligrams-daily-in-patients-with-pulmonary-tuberculosis
#18
R E Aarnoutse, G S Kibiki, K Reither, H H Semvua, F Haraka, C M Mtabho, S G Mpagama, J van den Boogaard, I M Sumari-de Boer, C Magis-Escurra, M Wattenberg, J G M Logger, L H M Te Brake, M Hoelscher, S H Gillespie, A Colbers, P P J Phillips, G Plemper van Balen, M J Boeree
In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months...
November 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28817561/comparing-efficacies-of-moxifloxacin-levofloxacin-and-gatifloxacin-in-tuberculosis-granulomas-using-a-multi-scale-systems-pharmacology-approach
#19
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/28803492/rifampin-vs-rifapentine-what-is-the-preferred-rifamycin-for-tuberculosis
#20
REVIEW
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...
October 2017: Expert Review of Clinical Pharmacology
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