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pharmacokinetics and TB

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https://www.readbyqxmd.com/read/28719501/evaluation-of-the-adequacy-of-the-2010-revised-world-health-organization-recommended-dosages-of-the-first-line-antituberculosis-drugs-for-children
#1
Hongmei Yang, Anthony Enimil, Fizza S Gillani, Sampson Antwi, Albert Dompreh, Antoinette Ortsin, Eugene Adu Awhireng, Maxwell Owusu, Lubbe Wiesner, Charles A Peloquin, Awewura Kwara
BACKGROUND: The World Health Organization recommended increased dosages of the first-line antituberculosis (anti-TB) drugs for children in 2010. We examined the frequency of and factors associated with low plasma maximum concentration (Cmax) of each drug in children treated with the revised dosages. METHODS: Children on anti-TB therapy for at least 4 weeks underwent pharmacokinetic testing. Plasma Cmax below the lower limit of proposed reference range was considered low...
July 14, 2017: Pediatric Infectious Disease Journal
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
#2
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
#3
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/28623874/lansoprazole-sulfide-pharmacokinetics-of-this-promising-anti-tuberculous-agent
#4
Sipho Mdanda, Sooraj Baijnath, Adeola Shobo, Sanil D Singh, Glenn E M Maguire, Hendrik G Kruger, Per I Arvidsson, Tricia Naicker, Thavendran Govender
Lansoprazole (LPZ) is a commercially available proton-pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis. It was also reported that a 300 mg kg(-1) oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed...
June 17, 2017: Biomedical Chromatography: BMC
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
#5
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-optimising-dosing-regimens-for-drug-sensitive-and-resistant-tuberculosis
#6
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 sterilising effect against tubercle bacilli allows treatment shortening. 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 multi-drug resistant tuberculosis(MDR-TB)...
June 12, 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
#7
Shashikant Srivastava, Gesham Magombedze, Thearith Koeuth, Carleton Sherman, Jotam G Pasipanodya, Prithvi Raj, Edward Wakeland, Devyani Deshpande, Tawanda Gumbo
Linezolid has 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...
June 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28570367/antiretroviral-dose-optimization-the-future-of-efavirenz-400%C3%A2-mg-dosing
#8
Marta Boffito, Mohammed Lamorde, Melynda Watkins, Anton Pozniak
PURPOSE OF REVIEW: Antiretroviral (ARV) therapy costs in low-income and middle-income countries are major concerns, and lower doses of first-line treatment components, when possible, would save millions of dollars, which could be used to treat more people living with HIV. RECENT FINDINGS: The Encore-1 study, followed by a detailed pharmacokinetic analysis of efavirenz 400 versus 600 mg once daily, produced enough information for the most recent ARV treatment WHO guidelines to include efavirenz 400 mg among agents used for first-line treatment...
July 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28561946/new-paradigm-for-translational-modeling-to-predict-long-term-tuberculosis-treatment-response
#9
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/28559276/population-pharmacokinetic-model-linking-plasma-and-peripheral-blood-mononuclear-cells-pbmcs-concentrations-of-efavirenz-and-its-metabolite-8-hydroxy-efavirenz-in-hiv-patients
#10
Abiy Habtewold, Eleni Aklillu, Eyasu Makonnen, Getnet Yimer, Leif Bertilsson, Jürgen Burhenne, Joel S Owen
Objectives: To characterize the population PK of EFV and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and explore covariates affecting the PK parameters.Methods: Fifty-one patients had steady-state 0-24h plasma with corresponding PBMC concentrations of EFV and 8OHEFV, while 261 patients had 1 or 2 sparse concentrations at 16±1h post-dose at weeks 4 and/or 16. Pharmacogenetic markers CYP2B6*6, CYP3A5 (*3 &*6);, UGT2B7*2, ABCB1 (3435C<T, 3842A<G), OATP1B1 (*1B & *5), presence of rifampicin-based anti-TB regimen, baseline body weight and organ function values; and demographic factors were explored as covariates...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28546104/development-of-a-paediatric-physiologically-based-pharmacokinetic-model-to-assess-the-impact-of-drug-drug-interactions-in-tuberculosis-co-infected-malaria-subjects-a-case-study-with-artemether-lumefantrine-and-the-cyp3a4-inducer-rifampicin
#11
Olusola Olafuyi, Michael Coleman, Raj K S Badhan
The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs); indeed, knowledge of the impact of these factors is currently sparse in paediatric population groups. Confounding malaria treatment is the co-infection of patients with tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure...
August 30, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28520930/improved-power-for-tb-phase-iia-trials-using-a-model-based-pharmacokinetic-pharmacodynamic-approach-compared-with-commonly-used-analysis-methods
#12
Robin J Svensson, Stephen H Gillespie, Ulrika S H Simonsson
Background: The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process. Objectives: To explore the power to find statistically significant drug effects using a model-based pharmacokinetic-pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials. Methods: Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model...
May 16, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28510418/conjugation-reaction-with-8-arm-peg-markedly-improves-the-immunogenicity-of-mycobacterium-tuberculosis-cfp10-tb10-4-fusion-protein
#13
Xiaowei Sun, Weili Yu, Quanhai Pang, Tao Hu
Mycobacterium tuberculosis (Mtb) is a serious fatal pathogen responsible for tuberculosis (TB). Effective vaccination is highly desired for immunoprotection against Mtb infection. CFP10 and TB10.4 are two important immunodominant Mtb-secreted protein antigens, which suffer from poor immunogenicity. Thus, an antigen delivery system and adjuvants are needed to improve the immunogenicity of the two proteins. A CFP10-TB10.4 fusion protein (CT) was used as the antigen in the present study. Conjugation of 4-6 CT molecules in one entity with 8-arm polyethylene glycol (PEG) acted as an antigen delivery system...
June 21, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28507117/pharmacokinetics-of-levofloxacin-in-multidrug-and-extensively-drug-resistant-tuberculosis-patients
#14
Natasha Van't Boveneind-Vrubleuskaya, Tatiana Seuruk, Kai van Hateren, Tridia van der Laan, Jos G W Kosterink, Tjip S van der Werf, Dick van Soolingen, Susan van den Hof, Alena Skrahina, Jan-Willem C Alffenaar
Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily...
May 15, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28472448/markers-of-gut-dysfunction-do-not-explain-low-rifampicin-bioavailability-in-hiv-associated-tb
#15
Christopher Vinnard, Shruthi Ravimohan, Neo Tamuhla, Jotam Pasipanodya, Shashikant Srivastava, Chawangwa Modongo, Nicola M Zetola, Drew Weissman, Tawanda Gumbo, Gregory P Bisson
Background: Rifampicin is the key drug responsible for sterilizing activities in the first-line TB treatment regimen. Damage to the gut during acute and chronic HIV infection may inhibit drug absorptive capacity. We sought to test the hypothesis that markers of intestinal damage, bacterial translocation and systemic immune activation would relate to rifampicin bioavailability among HIV/TB patients. Patients and methods: We conducted a prospective cohort study of rifampicin pharmacokinetics in HIV/TB patients in Gaborone, Botswana...
May 2, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28461315/genetic-determinants-of-the-pharmacokinetic-variability-of-rifampin-in-malawian-adults-with-pulmonary-tuberculosis
#16
Derek J Sloan, Andrew D McCallum, Alessandro Schipani, Deirdre Egan, Henry C Mwandumba, Steve A Ward, David Waterhouse, Gertrude Banda, Theresa J Allain, Andrew Owen, Saye H Khoo, Geraint R Davies
Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose...
July 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28423019/design-synthesis-and-structure-activity-relationship-study-of-wollamide-b-a-new-potential-anti-tb-agent
#17
Henok Asfaw, Katja Laqua, Anna Maria Walkowska, Fraser Cunningham, Maria Santos Martinez-Martinez, Juan Carlos Cuevas-Zurita, Lluís Ballell-Pages, Peter Imming
Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 μM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness...
2017: PloS One
https://www.readbyqxmd.com/read/28419277/prevention-of-tb-using-rifampicin-plus-isoniazid-reduces-nevirapine-concentrations-in-hiv-exposed-infants
#18
Helen McIlleron, Paolo Denti, Silvia Cohn, Fildah Mashabela, Jennifer D Hoffmann, Saba Shembe, Regina Msandiwa, Lubbe Wiesner, Sithembiso Velaphi, Sanjay G Lala, Richard E Chaisson, Neil Martinson, Kelly E Dooley
Background: Newborns of HIV-infected mothers are given daily doses of nevirapine to prevent HIV-1 acquisition. Infants born to mothers with TB should also receive TB preventive therapy. TB preventive regimens include isoniazid for 6 months or rifampicin plus isoniazid for 3 months (RH preventive therapy). The effect of concomitant RH preventive therapy on nevirapine concentrations in infants is unknown. Patients and methods: Tshepiso was a prospective case-control cohort study of pregnant HIV-infected women with and without TB whose newborn infants received standard doses of nevirapine for HIV prophylaxis...
April 16, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28408267/population-pharmacokinetics-of-moxifloxacin-cycloserine-p-aminosalicylic-acid-and-kanamycin-for-the-treatment-of-multi-drug-resistant-tuberculosis
#19
Min Jung Chang, Byunghak Jin, Jung-Woo Chae, Hwi-Yeol Yun, Eun Sun Kim, Yeon Joo Lee, Young-Jae Cho, Ho Il Yoon, Choon-Taek Lee, Kyoung Un Park, Junghan Song, Jae-Ho Lee, Jong Sun Park
Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients...
June 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28389352/simple-strategy-to-assess-linezolid-exposure-in-patients-with-multi-drug-resistant-and-extensively-drug-resistant-tuberculosis
#20
Jasper Kamp, Mathieu S Bolhuis, Simon Tiberi, Onno W Akkerman, Rosella Centis, Wiel C de Lange, Jos G Kosterink, Tjip S van der Werf, Giovanni B Migliori, Jan-Willem C Alffenaar
Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed to develop a population pharmacokinetic model to predict the area under the concentration curve (AUC) for linezolid using a limited number of blood samples. Data from patients with MDR-/XDR-TB who received linezolid and therapeutic drug monitoring as part of their TB treatment were used...
June 2017: International Journal of Antimicrobial Agents
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