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Antimicrobial Agents and Chemotherapy Jun 2021Pyrazinamide is a first-line drug used in the treatment of tuberculosis. High exposure to pyrazinamide and its metabolites may result in hepatotoxicity, whereas low...
Pyrazinamide is a first-line drug used in the treatment of tuberculosis. High exposure to pyrazinamide and its metabolites may result in hepatotoxicity, whereas low exposure to pyrazinamide has been correlated with treatment failure of first-line antitubercular therapy. The aim of this study was to describe the pharmacokinetics and metabolism of pyrazinamide in patients coinfected with tuberculosis and HIV. We further aimed to identify demographic and clinical factors which affect the pharmacokinetics of pyrazinamide and its metabolites in order to suggest individualized dosing regimens. Plasma concentrations of pyrazinamide, pyrazinoic acid, and 5-hydroxypyrazinamide from 63 Rwandan patients coinfected with tuberculosis and HIV were determined by liquid chromatography-tandem mass spectrometry followed by nonlinear mixed-effects modeling. Females had a close to 50% higher relative pyrazinamide bioavailability compared to males. The distribution volumes of pyrazinamide and both metabolites were lower in patients on concomitant efavirenz-based HIV therapy. Furthermore, there was a linear relationship between serum creatinine and oral clearance of pyrazinoic acid. Simulations indicated that increasing doses from 25 mg/kg of body weight to 35 mg/kg and 50 mg/kg in females and males, respectively, would result in adequate exposure with regard to suggested thresholds and increase probability of target attainment to >0.9 for a MIC of 25 mg/liter. Further, lowering the dose by 40% in patients with high serum creatinine would prevent accumulation of toxic metabolites. Individualized dosing is proposed to decrease variability in exposure to pyrazinamide and its metabolites. Reducing the variability in exposure may lower the risk of treatment failure and resistance development.
Topics: Antitubercular Agents; Coinfection; Female; HIV Infections; Humans; Male; Pyrazinamide; Tuberculosis
PubMed: 33875424
DOI: 10.1128/AAC.00046-21 -
Antimicrobial Agents and Chemotherapy Feb 2020Tuberculosis is an important cause of maternal morbidity, but little is known about the effects of pregnancy on antituberculosis drug concentrations. We developed...
Tuberculosis is an important cause of maternal morbidity, but little is known about the effects of pregnancy on antituberculosis drug concentrations. We developed population pharmacokinetic models to describe drug dispositions of isoniazid, pyrazinamide, and ethambutol in pregnant women with tuberculosis and HIV. HIV-positive pregnant women with tuberculosis receiving standard first-line tuberculosis treatment and participating in Tshepiso, a prospective cohort study in Soweto, South Africa, underwent sparse pharmacokinetic sampling at >36 weeks of gestation and 7 weeks postpartum. The effects of pregnancy on the pharmacokinetics of isoniazid, pyrazinamide, and ethambutol were investigated via population pharmacokinetic modeling. Isoniazid, pyrazinamide, and ethambutol concentrations were available for 29, 18, and 18 women, respectively. Their median weight was 66 kg while pregnant and 64 kg postpartum. No significant differences were observed in drug clearance, volume of distribution, or bioavailability during and after pregnancy. The model-estimated isoniazid, pyrazinamide, and ethambutol area under the concentration-time curve from 0 to 24 h (AUC) medians were, respectively, 6.88, 419, and 16.5 mg · h/liter during pregnancy versus 5.01, 407, and 19.0 mg · h/liter postpartum. The model-estimated maximum concentration () medians for isoniazid, pyrazinamide, and ethambutol were, respectively, 1.39, 35.9, and 1.82 mg/liter during pregnancy versus 1.43, 34.5, and 2.11 mg/liter postpartum. power calculations determined that our analysis was powered 91.8%, 59.2%, and 90.1% at a of <0.01 to detect a 40% decrease in the AUCs of isoniazid, pyrazinamide, and ethambutol, respectively. Pregnancy does not appear to cause relevant changes in the exposure to isoniazid, pyrazinamide, and ethambutol. Additional studies of antituberculosis drugs in pregnancy are needed.
Topics: Adult; Antitubercular Agents; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Pregnancy; Prospective Studies; Pyrazinamide; Tuberculosis, Pulmonary; Young Adult
PubMed: 31844002
DOI: 10.1128/AAC.01978-19 -
EBioMedicine Nov 2019Pyrazinamide remains the only drug in the tuberculosis pharmacopeia to drastically shorten first-line therapy from nine to six months. Due to its unparalleled ability to... (Review)
Review
Pyrazinamide remains the only drug in the tuberculosis pharmacopeia to drastically shorten first-line therapy from nine to six months. Due to its unparalleled ability to sterilize non-replicating bacilli and reduce relapse rates, PZA is expected to be irreplaceable in future therapies against tuberculosis. While the molecular target of PZA is unclear, recent pharmacokinetic studies using small animal models and patient samples have highlighted the importance of host metabolism and immune responses in PZA efficacy. Delineating which host factors are important for PZA action will be integral to the design of next-generation therapies to shorten current TB drug regimens as well as to overcome treatment limitations in some patients. In this review, we discuss evidence for influence of the host environment on PZA activity, targets for PZA mechanism of action, recent studies in PZA pharmacokinetics, PZA antagonism and synergy with other first-line anti-TB drugs, and implications for future research.
Topics: Animals; Antitubercular Agents; Host-Pathogen Interactions; Humans; Molecular Targeted Therapy; Mycobacterium tuberculosis; Pyrazinamide
PubMed: 31669220
DOI: 10.1016/j.ebiom.2019.10.014 -
Antimicrobial Agents and Chemotherapy Nov 2018Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c...
Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment. The effect of DM and HbA1c values on the maximum concentration () of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed. Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in the of pyrazinamide and isoniazid (but not rifampin) with DM or increasing HbA1c values. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations (adjusted geometric mean ratio = 0.74, = 0.03). In adjusted Cox models, female gender (adjusted hazards ratio [aHR] = 1.75, = 0.001), a lower smear grade with the Xpert assay (aHR = 1.40, < 0.001), and the pyrazinamide (aHR = 0.99, = 0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampin concentrations were associated with a faster time to culture conversion in patients with DM only. A pyrazinamide above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) (odds ratio = 1.92, = 0.04). DM and higher HbA1c values increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampin.
Topics: Adult; Antitubercular Agents; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Sputum; Tuberculosis, Pulmonary; Young Adult
PubMed: 30126955
DOI: 10.1128/AAC.01383-18 -
The European Respiratory Journal Sep 2020The World Health Organization recommends supervising the treatment of tuberculosis. Intermittent regimens have the potential to simplify the supervision and improve...
BACKGROUND
The World Health Organization recommends supervising the treatment of tuberculosis. Intermittent regimens have the potential to simplify the supervision and improve compliance. Our objective was to analyse the sterilising activity of once-weekly regimens based on drugs with a long half-life, bedaquiline and rifapentine, in a murine model of tuberculosis.
METHODS
300 Swiss mice were infected intravenously infected with ×10 CFU H37Rv. Mice were treated once weekly with regimens containing: 1) bedaquiline, rifapentine and pyrazinamide (BPZ); 2) BPZ plus moxifloxacin (BPZM); 3) BPZM plus clofazimine (BPZMC); 4) the standard daily regimen of tuberculosis. All regimens were given for 4 or 6 months. Bactericidal and sterilising activity were assessed.
RESULTS
After 2 months of treatment, the mean count in lungs was 0.76±0.60 log CFU in mice treated with the daily control regimen and negative in all mice treated with once-weekly regimens (p<0.05 compared to the daily control). All mice had negative lung cultures on completion of either 4 or 6 months of treatment, whereas 3 months after 4 and 6 months of treatment, respectively, the relapse rate was 64% and 13% in the standard daily regimen, 5% and 0% in BPZ, 0% and 0% in BPMZ and 0% and 5% in BPMZC (p<0.05 for all once-weekly regimens 4-month daily control; p>0.05 for all once-weekly regimens 6-month daily control).
CONCLUSIONS
BPZ-based once-weekly regimens have higher sterilising activity than the standard daily regimen and could greatly simplify treatment administration and possibly shorten the duration of tuberculosis treatment.
Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis
PubMed: 32430417
DOI: 10.1183/13993003.02502-2019 -
Bioinformatics (Oxford, England) May 2018Correct and rapid determination of Mycobacterium tuberculosis (MTB) resistance against available tuberculosis (TB) drugs is essential for the control and management of...
MOTIVATION
Correct and rapid determination of Mycobacterium tuberculosis (MTB) resistance against available tuberculosis (TB) drugs is essential for the control and management of TB. Conventional molecular diagnostic test assumes that the presence of any well-studied single nucleotide polymorphisms is sufficient to cause resistance, which yields low sensitivity for resistance classification.
SUMMARY
Given the availability of DNA sequencing data from MTB, we developed machine learning models for a cohort of 1839 UK bacterial isolates to classify MTB resistance against eight anti-TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, ciprofloxacin, moxifloxacin, ofloxacin, streptomycin) and to classify multi-drug resistance.
RESULTS
Compared to previous rules-based approach, the sensitivities from the best-performing models increased by 2-4% for isoniazid, rifampicin and ethambutol to 97% (P < 0.01), respectively; for ciprofloxacin and multi-drug resistant TB, they increased to 96%. For moxifloxacin and ofloxacin, sensitivities increased by 12 and 15% from 83 and 81% based on existing known resistance alleles to 95% and 96% (P < 0.01), respectively. Particularly, our models improved sensitivities compared to the previous rules-based approach by 15 and 24% to 84 and 87% for pyrazinamide and streptomycin (P < 0.01), respectively. The best-performing models increase the area-under-the-ROC curve by 10% for pyrazinamide and streptomycin (P < 0.01), and 4-8% for other drugs (P < 0.01).
AVAILABILITY AND IMPLEMENTATION
The details of source code are provided at http://www.robots.ox.ac.uk/~davidc/code.php.
CONTACT
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Antitubercular Agents; Ciprofloxacin; Ethambutol; Humans; Isoniazid; Machine Learning; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Pyrazinamide; Rifampin; Sequence Analysis, DNA; Streptomycin; Tuberculosis, Multidrug-Resistant
PubMed: 29240876
DOI: 10.1093/bioinformatics/btx801 -
Nature Communications Dec 2023The antibiotic pyrazinamide (PZA) is a cornerstone of tuberculosis (TB) therapy that shortens treatment durations by several months despite being only weakly...
The antibiotic pyrazinamide (PZA) is a cornerstone of tuberculosis (TB) therapy that shortens treatment durations by several months despite being only weakly bactericidal. Intriguingly, PZA is also an anti-inflammatory molecule shown to specifically reduce inflammatory cytokine signaling and lesion activity in TB patients. However, the target and clinical importance of PZA's host-directed activity during TB therapy remain unclear. Here, we identify the host enzyme Poly(ADP-ribose) Polymerase 1 (PARP1), a pro-inflammatory master regulator strongly activated in TB, as a functionally relevant host target of PZA. We show that PZA inhibits PARP1 enzymatic activity in macrophages and in mice where it reverses TB-induced PARP1 activity in lungs to uninfected levels. Utilizing a PZA-resistant mutant, we demonstrate that PZA's immune-modulatory effects are PARP1-dependent but independent of its bactericidal activity. Importantly, PZA's bactericidal efficacy is impaired in PARP1-deficient mice, suggesting that immune modulation may be an integral component of PZA's antitubercular activity. In addition, adjunctive PARP1 inhibition dramatically reduces inflammation and lesion size in mice and may be a means to reduce lung damage and shorten TB treatment duration. Together, these findings provide insight into PZA's mechanism of action and the therapeutic potential of PARP1 inhibition in the treatment of TB.
Topics: Humans; Animals; Mice; Pyrazinamide; Mycobacterium tuberculosis; Antitubercular Agents; Tuberculosis; Anti-Inflammatory Agents; Microbial Sensitivity Tests; Poly (ADP-Ribose) Polymerase-1
PubMed: 38071218
DOI: 10.1038/s41467-023-43937-1 -
Clinical Infectious Diseases : An... May 2017There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD)...
BACKGROUND
There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.
METHODS
One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).
RESULTS
Twenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.
CONCLUSIONS
PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.
Topics: Adult; Antitubercular Agents; Coinfection; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary
PubMed: 28205671
DOI: 10.1093/cid/cix158 -
Clinical Infectious Diseases : An... Mar 2020The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood.
BACKGROUND
The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood.
METHODS
We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models.
RESULTS
Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]).
CONCLUSIONS
Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.
Topics: Antitubercular Agents; Humans; India; Isoniazid; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis
PubMed: 31075166
DOI: 10.1093/cid/ciz380 -
CPT: Pharmacometrics & Systems... Nov 2021Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration... (Review)
Review
Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration of treatment. The purpose of this study was to demonstrate utility of a physiologically-based pharmacokinetic modeling approach to predict plasma and lung concentrations of 11 compounds used or under development as TB therapies (bedaquiline [and N-desmethyl bedaquiline], clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, pyrazinamide, rifampicin, and rifapentine). Model accuracy was assessed by comparison of simulated plasma pharmacokinetic parameters with healthy volunteer data for compounds administered alone or in combination. Eighty-four percent (area under the curve [AUC]) and 91% (maximum concentration [C ]) of simulated mean values were within 1.5-fold of the observed data and the simulated drug-drug interaction ratios were within 1.5-fold (AUC) and twofold (C ) of the observed data for nine (AUC) and eight (C ) of the 10 cases. Following satisfactory recovery of plasma concentrations in healthy volunteers, model accuracy was assessed further (where patients' with TB data were available) by comparing clinical data with simulated lung concentrations (9 compounds) and simulated lung: plasma concentration ratios (7 compounds). The 5th-95th percentiles for the simulated lung concentration data recovered between 13% (isoniazid and pyrazinamide) and 88% (pyrazinamide) of the observed data points (Am J Respir Crit Care Med, 198, 2018, 1208; Nat Med, 21, 2015, 1223; PLoS Med, 16, 2019, e1002773). The impact of uncertain model parameters, such as the fraction of drug unbound in lung tissue mass (fu ), is discussed. Additionally, the variability associated with the patient lung concentration data, which was sparse and included extensive within-subject, interlaboratory, and experimental variability (as well interindividual variability) is reviewed. All presented models are transparently documented and are available as open-source to aid further research.
Topics: Antitubercular Agents; Humans; Isoniazid; Pyrazinamide; Standard of Care; Tuberculosis
PubMed: 34623770
DOI: 10.1002/psp4.12707