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pharmacokinetics And tuberculosis drugs

Charles A Peloquin, Patrick P J Phillips, Carole D Mitnick, Kathleen Eisenach, Ramonde F Patientia, Leonid Lecca, Eduardo Gotuzzo, Neel R Gandhi, Donna Butler, Andreas H Diacon, Bruno Martel, Juan Santillan, Kathleen Robergeau Hunt, Dante Vargas, Florian von Groote-Bidlingmaier, Carlos Seas, Nancy Dianis, Antonio Moreno-Martinez, Pawandeep Kaur, C Robert Horsburgh
Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to weight-banded nominal doses of 11, 14, 17 or 20 mg/kg/day levofloxacin (minimum 750 mg) in combination with other second-line agents. 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median AUC0-24 were 109.49, 97.86, 145.33 and 207.04 h*mcg/ml. Median Cmax were 11.90, 12.02, 14.86, and 19.17 mcg/ml. Higher levofloxacin doses, up to 1500 mg daily, resulted in higher exposures. ClinicalTrials...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Deborah Ford, Rebecca Turner, Anna Turkova, Martina Penazzato, Victor Musiime, Mutsa Bwakura-Dangarembizi, Avy Violari, Chishala Chabala, Thanyawee Puthanakit, Tavitiya Sudjaritruk, Tim R Cressey, Marc Lallemant, Diana M Gibb
For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission...
August 15, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
R K R Rajoli, A T Podany, D M Moss, S Swindells, C Flexner, A Owen, M Siccardi
SETTING: Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues. OBJECTIVE: niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI). DESIGN: PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution...
August 1, 2018: International Journal of Tuberculosis and Lung Disease
Elise D Pieterman, Lindsey H M Te Brake, Gerjo J de Knegt, Aart van der Meijden, Jan-Willem C Alffenaar, Hannelore I Bax, Rob E Aarnoutse, Jurriaan E M de Steenwinkel
Favorable treatment outcome of multidrug resistant tuberculosis (MDR-TB) is only 54% and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the additional value of the efflux-pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug sensitive Mycobacterium tuberculosis and were treated with human-equivalent doses of moxifloxacin (200 mg/kg) and linezolid (100 mg/kg) with or without verapamil (12...
July 9, 2018: Antimicrobial Agents and Chemotherapy
Prakash Khadka, Jack Dummer, Philip C Hill, Shyamal C Das
Drug delivery via the inhaled route has advantages for treating local and systemic diseases. Pulmonary drug delivery may have potential in treating tuberculosis (TB), which is mainly localised in the lung (pulmonary tuberculosis ∼75%) while also affecting other organs (extra-pulmonary tuberculosis). Currently, rifampicin, a first-line anti-tubercular drug, is given orally and the maximum daily oral dose is the lesser of 10 mg/kg or 600 mg. Since only a small fraction of this dose is available in the lung, concentrations may frequently fail to reach bactericidal levels, and therefore, contribute to the development of multi-drug resistant pulmonary TB...
July 3, 2018: International Journal of Pharmaceutics
Samuel K Kwofie, Bismark Dankwa, Emmanuel A Odame, Francis E Agamah, Lady P A Doe, Joshua Teye, Odame Agyapong, Whelton A Miller, Lydia Mosi, Michael D Wilson
Buruli ulcer (BU) is caused by Mycobacterium ulcerans and is predominant in both tropical and subtropical regions. The neglected debilitating disease is characterized by chronic necrotizing skin lesions attributed to a mycolactone, which is a macrolide toxin secreted by M. ulcerans . The preferred treatment is surgical excision of the lesions followed by a prolonged combination antibiotic therapy using existing drugs such as rifampicin and streptomycin or clarithromycin. These antibiotics appear not to be adequately potent and efficacious against persistent and late stage ulcers...
June 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Elin M Svensson, Jeannine du Bois, Rene Kitshoff, Veronique R de Jager, Lubbe Wiesner, Jennifer Norman, Sharon Nachman, Betsy Smith, Andreas Diacon, Anneke C Hesseling, Anthony J Garcia-Prats
OBJECTIVES: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers...
June 27, 2018: British Journal of Clinical Pharmacology
Mwila Mulubwa, Pierre Mugabo
The first chromatographic method (HPLC-UV) has been developed and validated for analysis of terizidone in plasma. Terizidone was extracted from plasma by protein precipitation process using a mixture of acetonitrile and methanol (1:1, v/v). The chromatographic separation was achieved with a gradient of acetonitrile and water both containing 0.1% formic acid on Supelco Discovery® HS C-18 (150 mm x 4.6 mm, 5μm) reversed-phase column. Propranolol was used as internal standard (IS). The total run-time was 18 minutes...
June 26, 2018: Biomedical Chromatography: BMC
Lloyd Tanner, Paolo Denti, Lubbe Wiesner, Digby F Warner
Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism...
June 22, 2018: IUBMB Life
Elin M Svensson, Robin J Svensson, Lindsey H M Te Brake, Martin J Boeree, Norbert Heinrich, Sarah Konsten, Gavin Churchyard, Rodney Dawson, Andreas H Diacon, Gibson S Kibiki, Lilian T Minja, Nyanda E Ntingiya, Ian Sanne, Stephen H Gillespie, Michael Hoelscher, Patrick P J Phillips, Ulrika S H Simonsson, Rob Aarnoutse
Background: Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods: Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg...
June 18, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Yasuhiro Horita, Abdullah Alsultan, Awewura Kwara, Sampson Antwi, Antony Enimil, Antoinette Orstin, Albert Dompreh, Hongmei Yang, Lubbe Wiesner, Charles A Peloquin
Optimal doses for anti-tuberculosis (TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosages ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) for at least 4 weeks had blood samples collected at pre-dose, 1, 2, 4, and 8-hours post-dose...
June 18, 2018: Antimicrobial Agents and Chemotherapy
Keertan Dheda, Laura Lenders, Gesham Magombedze, Shashikant Srivastava, Prithvi Raj, Erland Arning, Paula Ashcraft, Teodoro Bottiglieri, Helen Wainwright, Timothy Pennel, Anthony Linegar, Loven Moodley, Anil Pooran, Jotam G Pasipanodya, Frederick A Sirgel, Paul D van Helden, Edward Wakeland, Robin M Warren, Tawanda Gumbo
RATIONALE: Acquired resistance is an important driver of multidrug-resistant tuberculosis, even with good treatment adherence. However, exactly what initiates the resistance, and how it arises remains poorly understood. OBJECTIVES: To identify the relationship between drug concentrations and drug susceptibility readouts (MICs) in the tuberculosis cavity. METHODS: We recruited patients with medically incurable tuberculosis who were undergoing therapeutic lung resection whilst on treatment with the cocktail of second line anti-tuberculosis drugs...
June 7, 2018: American Journal of Respiratory and Critical Care Medicine
Imran H Khan, Navin B Patel, Vatsal M Patel
BACKGROUND: A series of (E)-5-(4-((Z)-4-substitutedbenzylidene/2-thienylmethylene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl) benzylidene)thiazolidine-2,4-dione were synthesized and evaluated for antimycobacterial and antimicrobial activity. All these ligands were docked against protein (InhA) Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, (PDB ID: 4COD). OBJECTIVE: In this report we have designed and synthesized azole scaffolds with good antitubercular activities as there is a real need to develop new candidates with less toxicity and more efficient toward pathogen...
May 15, 2018: Current Computer-aided Drug Design
Bruno L Abbadi, Valnês da Silva Rodrigues-Junior, Adilio da Silva Dadda, Kenia Pissinate, Anne D Villela, Maria M Campos, Luiz G de França Lopes, Cristiano V Bizarro, Pablo Machado, Eduardo H S Sousa, Luiz A Basso
The emergence of strains of Mycobacterium tuberculosis resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial katG -encoded catalase-peroxidase, forming an acylpyridine fragment that is covalently attached to the C4 of NADH. This isonicotinyl-NAD adduct inhibits the activity of 2- trans -enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis. A metal-based INH analog, Na3 [FeII (CN)5 (INH)]·4H2 O, IQG-607, was designed to have an electronic redistribution on INH moiety that would lead to an intramolecular electron transfer to bypass KatG activation...
2018: Frontiers in Microbiology
Lisa C Martial, Jordy Kerkhoff, Nilza Martinez, Mabel Rodríguez, Rosarito Coronel, Gladys Molinas, Myriam Roman, Roscio Gomez, Sarita Aguirre, Erwin Jongedijk, Justine Huisman, Daan J Touw, Domingo Pérez, Gilberto Chaparro, Felipe Gonzalez, Rob E Aarnoutse, Jan-Willem Alffenaar, Cecile Magis-Escurra
BACKGROUND: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. METHODS: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol...
May 8, 2018: International Journal of Antimicrobial Agents
Sauzanne G Khalilieh, Ka Lai Yee, Rosa I Sanchez, Rachel Liu, Li Fan, Maureen Martell, Heather Jordan, Marian Iwamoto
Doravirine is a nonnucleoside reverse transcriptase inhibitor in clinical development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretroviral therapies. The cytochrome P450 (CYP)3A-dependent metabolism of doravirine makes it susceptible to interactions with modulators of this pathway, including the antituberculosis treatment rifampin. Rifabutin, an alternative antibiotic used to treat tuberculosis, may have a lower-magnitude effect on CYP3A. The aim of this trial was to determine the effect of steady-state rifabutin on doravirine single-dose pharmacokinetics and tolerability...
May 3, 2018: Journal of Clinical Pharmacology
Robert S Wallis, Caryn E Good, Mary A O'Riordan, Jeffrey L Blumer, Michael R Jacobs, J McLeod Griffiss, Amanda Healan, Robert A Salata
BACKGROUND: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture...
2018: PloS One
Emílio V Lage, Joana Magalhães, Marina Pinheiro, Salette Reis
In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism...
June 1, 2018: Chemico-biological Interactions
Marlanka A Zuur, Jotam G Pasipanodya, Dick van Soolingen, Tjip S van der Werf, Tawanda Gumbo, Jan-Willem C Alffenaar
Background: In infectious diseases, for some drugs, bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to anti-tuberculosis drugs. Pharmacokinetics/pharmacodynamics (PK/PD) target exposures, in tandem with Monte Carlo experiments (MCE), recently identified susceptibility breakpoints of 0...
April 24, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Antonia Morita Iswari Saktiawati, Yanri Wijayanti Subronto
BACKGROUND: the correlation between diabetes mellitus (DM) and Multi-Drug-Resistant Tuberculosis (MDR-TB) has never been studied among patients with tuberculosis (TB) in Indonesia, while DM has been identified to alter immune response and pharmacokinetics of TB medications that may lead to a failure of TB treatment and develop MDR-TB. Our study aimed to analyze the influence of diabetes mellitus on the development of MDR-TB. METHODS: a retrospective cohort study was carried out on 356 TB patients at the Provincial Lung Clinics and Sardjito Hospital, Yogyakarta, Indonesia between 2010 and 2014...
January 2018: Acta Medica Indonesiana
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