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pharmacokinetics And tuberculosis drugs

Anushka Naidoo, Maxwell Chirehwa, Veron Ramsuran, Helen McIlleron, Kogieleum Naidoo, Nonhlanhla Yende-Zuma, Ravesh Singh, Sinaye Ncgapu, John Adamson, Katya Govender, Paolo Denti, Nesri Padayatchi
AIM: We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin. MATERIALS & METHODS: Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics. RESULTS: Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively...
February 15, 2019: Pharmacogenomics
Kazunari Tsuyuguchi, Yuka Sasaki, Satoshi Mitarai, Ken Kurosawa, Yuki Saito, Tadaishi Koh
BACKGROUND: Bedaquiline, a diarylquinoline with a novel mode of action that specifically inhibits mycobacterial adenosine 5׳-triphosphate (ATP) synthase, has been approved in over 50 countries including the USA and EU for the treatment of pulmonary multidrug-resistant tuberculosis (pMDR-TB) in adults. METHODS: This study was conducted to evaluate the safety, efficacy, and pharmacokinetics of bedaquiline in adult Japanese patients with pMDR-TB. In this study, patients received bedaquiline for 24 weeks or more (maximum 48 weeks) with an individualized background regimen (BR)...
February 7, 2019: Respiratory Investigation
Estella Dora Germaine Garessus, Hans Mielke, Ursula Gundert-Remy
Isoniazid is a first-line anti-tuberculosis drug recommended for treatment of drug-susceptible Mycobacterium tuberculosis infections. Breast-feeding is not contra-indicated while undergoing isoniazid therapy, even though isoniazid was found to migrate into breast milk, leading to infant drug exposure. Exposure assessment of isoniazid in infants exposed to the drug via breast milk has so far not accounted for the polymorphic expression of the isoniazid metabolising enzyme N -acetyltransferase 2. The aim of this study was to re-visit the safety assessment of maternal isoniazid therapy for infants exposed to the drug via breast milk, while accounting for fast and slow metabolisers in the adult and infant population, as well as for slower metabolism in small infants than in adults...
2019: Frontiers in Pharmacology
Akanksha Sharma, M Hayatul Islam, Nida Fatima, Tarun K Upadhyay, M Kalim A Khan, Upendra N Dwivedi, Rolee Sharma
Tuberculosis (TB) is a leading cause of mortality amongst infectious diseases. While the anti-TB drugs can cure TB, the non-compliance and rapidly increasing resistance is of serious concern. The study aimed to search novel potent inhibitor(s) against MabA and PKS18 targets of Mycobacterium tuberculosis (M.tb.) by virtual screening of anthraquinones from marine fungi. The target proteins MabA and PKS18 involved in M.tb. mycolic acid biosynthesis were retrieved from RCSB Protein Data Bank. Chemical structures of 100 marine fungal anthraquinones were retrieved from the PubChem database...
February 4, 2019: Molecular Biology Reports
Chetan Rathi, Pradeep B Lukka, Santosh Wagh, Richard E Lee, Anne J Lenaerts, Miriam Braunstein, Anthony Hickey, Mercedes Gonzalez-Juarrero, Bernd Meibohm
Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. Intrapulmonary aerosol (IPA) administration of lead spectinamide 1599 has previously been shown to be more efficacious than subcutaneous (SC) administration at comparable doses. The objective of the current study was to characterize the disposition of 1599 in plasma and lungs in mice in order to provide a potential rationale for the observed efficacy differences. 200 mg/kg of 1599 was administered to healthy BALB/c mice by SC injection or by IPA delivery...
January 2019: Tuberculosis
S Perrineau, M Lachâtre, M P Lê, C Rioux, P Loubet, M Fréchet-Jachym, M Cervantes Gonzales, N Grall, E Bouvet, N Veziris, Y Yazdanpanah, G Peytavin
SETTING: Bedaquiline (BDQ) has been approved for the treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). For many patients treatment is prolonged beyond the recommended 6 months. The long-term pharmacokinetics of BDQ have yet to be elucidated. OBJECTIVE: To evaluate plasma concentrations of BDQ during treatment and its elimination after treatment discontinuation. DESIGN: This was a retrospective study conducted in two units in France that provide treatment for MDR/XDR-TB...
January 1, 2019: International Journal of Tuberculosis and Lung Disease
Stijn W van Beek, Rob Ter Heine, Ron J Keizer, Cecile Magis-Escurra, Rob E Aarnoutse, Elin M Svensson
BACKGROUND AND OBJECTIVE: This study proposes a model-informed approach for therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB) treatment. METHODS: Two datasets from pulmonary TB patients were used: a pharmacokinetic study (34 patients, 373 samples), and TDM data (96 patients, 391 samples) collected at Radboud University Medical Center, The Netherlands. Nine suitable population pharmacokinetic models of rifampicin were identified in the literature and evaluated on the datasets...
January 23, 2019: Clinical Pharmacokinetics
Jose Francis, Simbarashe P Zvada, Paolo Denti, Mark Hatherill, Salome Charalambous, Stanley Mungofa, Rodney Dawson, Susan Dorman, Nikhil Gupte, Lubbe Wiesner, Amina Jindani, Thomas S Harrison, Adeniyi Olagunju, Deirdre Egan, Andrew Owen, Helen M McIlleron
Rifapentine is a rifamycin used to treat tuberculosis. As for rifampicin, plasma exposures of rifapentine are associated with treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, PXR, CAR, and AADAC on rifapentine exposure. Two studies evaluating novel regimens amongst Southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis...
January 22, 2019: Antimicrobial Agents and Chemotherapy
Matthew R Bockman, Curtis A Engelhart, Julia D Cramer, Michael Howe, Neeraj Mishra, Matthew Zimmerman, Peter Larson, Nadine Alvarez-Cabrera, Sae Woong Park, Helena I M Boshoff, James M Bean, Victor Young, David M Ferguson, Veronique Dartois, Joseph T Jarrett, Dirk Schnappinger, Courtney C Aldrich
The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of (S)-(-)-acidomycin is described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (MICs = 0.096-6.2 µM), but is inactive against non-tuberculosis mycobacteria, gram-positive and gram-negative pathogens (MICs > 1000 μM). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a Ki of approximately 1 µM through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosylmethionine (SAM) to generate the toxic metabolite 5'-deoxyadenosine...
January 17, 2019: ACS Infectious Diseases
A D Pranger, T S van der Werf, J G W Kosterink, J W C Alffenaar
The inability to use powerful antituberculosis drugs in an increasing number of patients seems to be the biggest threat towards global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug regimens are being investigated for pulmonary TB to counteract emergence of drug resistance. Intensified regimens with high-dose anti-TB drugs during the first weeks of treatment are being investigated for TB meningitis to increase the survival rate among these patients. Moxifloxacin, gatifloxacin and levofloxacin are seen as core agents in case of resistance or intolerance against first-line anti-TB drugs...
January 7, 2019: Drugs
Pierre Mugabo, Mwila Mulubwa
BACKGROUND AND OBJECTIVES: Pyrazinamide, a drug used in the regimen for the treatment of drug-sensitive tuberculosis, is also used for the treatment of multidrug-resistant tuberculosis (MDR-TB). We aimed to describe the population pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, in patients with MDR-TB and characterise the effects of demographic variables. METHODS: This was a non-randomised clinical study involving 51 adult patients admitted for the intensive phase of MDR-TB treatment...
January 8, 2019: European Journal of Drug Metabolism and Pharmacokinetics
Sean Wasserman, Paolo Denti, James C M Brust, Mahmoud Tareq, Siphokazi Hlungulu, Lubbe Wiesner, Jennifer Norman, Frederick A Sirgel, Robin M Warren, Aliasgar Esmail, Keertan Dheda, Neel R Gandhi, Graeme Meintjes, Gary Maartens
WHO recently recommended linezolid should be prioritized in treatment regimens for drug-resistant tuberculosis (TB), but there are limited data on its pharmacokinetics (PK) in this population. We conducted an observational study to explore covariate effects on linezolid PK and to estimate the probability of PK/pharmacodynamic target attainment in South African patients with drug-resistant TB. Consecutive adults on linezolid-based regimens were recruited in Cape Town and underwent intensive PK sampling at steady-state...
January 7, 2019: Antimicrobial Agents and Chemotherapy
Zeinab G Khalil, Timothy A Hill, Luis M De Leon Rodriguez, Rink-Jan Lohman, Huy N Hoang, Norbert Reiling, Doris Hillemann, Margaret A Brimble, David Fairlie, Antje Blumenthal, Robert J Capon
Wollamides are cyclic hexapeptides, recently isolated from an Australian soil Streptomyces, that exhibit promising in vitro anti-mycobacterial activity against Mycobacterium bovis Bacille Calmette Guérin, without displaying cytotoxicity against a panel of mammalian cells. Here, we report the synthesis and anti-mycobacterial activity of ×36 new synthetic wollamides, collated with all known synthetic and natural wollamides, to reveal structure characteristics responsible for in vitro growth inhibitory activity against Mycobacterium tuberculosis ( Mtb ) (H37Rv, H37Ra, CDC1551, HN878, HN353)...
January 2, 2019: Antimicrobial Agents and Chemotherapy
Blessed Winston Aruldhas, Richard M Hoglund, Jaya Ranjalkar, Joel Tarning, Sumith K Mathew, Valsan Philip Verghese, Anuradha Bose, Binu Susan Mathew
BACKGROUND: Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimise their dosing regimens. METHODS: Data were collected from 41 children, aged 2 to 16 years, who were being treated with anti-tuberculosis drugs for at least 2 months. Concentration measurements were done for a 6-hour period and analysed using a non-linear, mixed-effects model...
December 26, 2018: British Journal of Clinical Pharmacology
I Shah, N Jadhao, N Mali, S Deshpande, N Gogtay, U Thatte
<h2>OBJECTIVE:</h2>To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children.<h2>METHODS:</h2>INH levels were estimated using liquid chromatography-tandem mass spectroscopy in 35 children aged 1&ndash;15 years on daily anti-tuberculosis treatment. Blood samples were collected 0, 1, 2, 3, 6 and 24 h after INH administration. The maximum concentration (Cmax ) and area under the curve (AUC0&ndash;24 ) were determined. The normal therapeutic range for Cmax is 3&ndash;5 &mu;g/ml...
December 20, 2018: International Journal of Tuberculosis and Lung Disease
Pradeep Kumar, Glenn C Capodagli, Divya Awasthi, Riju Shrestha, Karishma Maharaja, Paridhi Sukheja, Shao-Gang Li, Daigo Inoyama, Matthew Zimmerman, Hsin Pin Ho Liang, Jansy Sarathy, Marizel Mina, George Rasic, Riccardo Russo, Alexander L Perryman, Todd Richmann, Aditi Gupta, Eric Singleton, Sheetal Verma, Seema Husain, Patricia Soteropoulos, Zhe Wang, Roxanne Morris, Gene Porter, Gautam Agnihotri, Padmini Salgame, Sean Ekins, Kyu Y Rhee, Nancy Connell, Véronique Dartois, Matthew B Neiditch, Joel S Freundlich, David Alland
We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure...
December 18, 2018: MBio
Pooja Mishra, Jaume Albiol-Chiva, Devasish Bose, Abhilasha Durgbanshi, Juan Peris-Vicente, Samuel Carda-Broch, Josep Esteve-Romero
Isoniazid is a drug that is widely used against tuberculosis. However, it shows high interpatient variability in metabolism kinetics and clinical effect, which complicates the prescription of the medication and jeopardizes the success of the therapy. Therefore, in a specific patient, the pharmacokinetics of the drug must be elucidated to decide the proper dosage and intake frequency to make the drug suitable for therapeutic drug monitoring. This can be performed by the quantification of the drug in urine as this process is non-invasive and allows the effects of long-time exposure to be inferred...
December 11, 2018: Antibiotics
Helena Rabie, Paolo Denti, Janice Lee, Mhleli Masango, Ashraf Coovadia, Sandy Pillay, Afaaf Liberty, François Simon, Helen McIlleron, Mark F Cotton, Marc Lallemant
BACKGROUND: Rifampicin reduces lopinavir concentrations in HIV and tuberculosis co-treated patients. We hypothesised that adding ritonavir to co-formulated lopinavir-ritonavir (4:1) to achieve a one-to-one ratio would overcome this drug-drug interaction in young children. METHODS: We did a prospective, open-label, one-group, one-sequence study at five sites in three South African provinces. We included HIV-infected children with tuberculosis, a bodyweight of 3-15 kg, and a post-conceptional age of more than 42 weeks...
December 6, 2018: Lancet HIV
Helen McIlleron, Maxwell T Chirehwa
Drug concentrations in tuberculosis patients on standard regimens vary widely with clinically important consequences. Areas covered: We review the available literature identifying factors correlated with pharmacokinetic variability of antituberculosis drugs. Based on population pharmacokinetic models and the weight, height and sex distributions in a large data base of African tuberculosis patients, we propose simplified weight-based doses of the available fixed dose combination(FDC) for adults with drug susceptible tuberculosis...
December 1, 2018: Expert Review of Anti-infective Therapy
Mathieu S Bolhuis, Onno W Akkerman, Marieke G G Sturkenboom, Samiksha Ghimire, Shashikant Srivastava, Tawanda Gumbo, Jan-Willem C Alffenaar
Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC)...
November 28, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
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