Tuberculosis pharmacokinetics

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...

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...

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...

Accumulating evidence suggest that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics and anti-mycobacterial 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 non-linear mixed effects modeling...

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...

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...

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...

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...

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)...

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...

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...

Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to 10, 15, and 20 mg/kg/day of rifampin. 168 had noncompartmental pharmacokinetic analyses: 67% were sampled twice; 33% six times. Doses were well-tolerated. Median (interquartile range) AUC0-6 was 24.9 (17.6-32.1), 43.1 (30.3-57.5), and 55.5 (35.7-73.2) h*mcg/mL; median Cmax in the experimental arms reached the target of 8 mcg/mL...

Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated...

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...

Pulmonary infections are common and caused by a wide range of viruses, bacteria, parasites and fungi. They consist of lower respiratory tract infections with community and hospital acquired acute pneumonia, bronchitis, lung abscess, fungal infections and tuberculosis. The management of these infections should be based on guidelines that take into account the microorganisms most frequently involved as a basis for empirical treatment, with identification of causative microorganisms allowing targeted treatments...

A novel series of fluorine-containing benzoxazinyl-oxazolidinones were designed and synthesized as antidrug-resistant tuberculosis agents possessing good activity and improved pharmacokinetic profiles. Compound 21 exhibited not only outstanding in vitro activity with a MIC value of 0.25-0.50 μg/mL against drug-susceptible H37Rv strain and two clinically isolated drug-resistant Mycobacterium tuberculosis strains, but also acceptable in vitro ADME/T properties. Moreover, this compound displayed excellent mouse pharmacokinetic profiles with an oral bioavailability of 102% and a longer elimination half-life of 4...

The eradication of tuberculosis disease requires drug regimens that can penetrate the multiple layers of complex pulmonary lesions. Drug distribution in the caseous cores of cavities and lesions is especially crucial because they harbor subpopulations of drug-tolerant bacteria also commonly referred to as persisters. Existing methods for the measurement of drug penetration in tuberculosis lesions involve costly and time-consuming in vivo pharmacokinetic studies coupled to bioanalytical or imaging techniques...

BACKGROUND: The delivery of antitubercular drugs through direct lung targeting can lead to reduction in the dose as well as side effects of the drug. In the present investigation, carrier (lactose)-based dry-powder inhaler of rifampicin was prepared to achieve direct targeting of the drug into the lungs. METHODS: The dry powder inhaler formulation was prepared by simply mixing micronized rifampicin with coarse and fine lactose preblend. Preliminary blends of the drug were prepared with various lactose grades (Inhalac(®), Respitose,(®) and Lactohale(®))...

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...

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...