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Helen Mcilleron - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of isoniazid pyrazinamide and Ethambutol in pregnant south african women with tuberculosis and hiv
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Mahmoud Tareq Abdelwahab, Rory Leisegang, Kelly E Dooley, Jyoti S Mathad, Lubbe Wiesner, Helen Mcilleron, Neil A Martinson, Ziyaad Waja, Matebogo Letutu, Richard E ChaissonAbstract: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 (AUC0-24) 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 (C max) 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. A posteriori power calculations determined that our analysis was powered 91.8%, 59.2%, and 90.1% at a P 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.
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population pharmacokinetics of Ethambutol in south african tuberculosis patients
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Siv Jonsson, Ulrika S. H. Simonsson, Alistair Davidse, Justin J Wilkins, Janstefan Van Der Walt, Mats O Karlsson, Pete Smith, Helen McilleronAbstract:Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of Ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with Ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of Ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to Ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of Ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.
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determinants of rifampin isoniazid pyrazinamide and Ethambutol pharmacokinetics in a cohort of tuberculosis patients
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Helen Mcilleron, Peter Wash, Andre Burger, Jennifer Norman, Peter I Folb, Peter J SmithAbstract:Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and Ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and Ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced Ethambutol concentrations; older patients had higher levels of isoniazid and Ethambutol; patients with a history of previous antituberculosis treatment had lower Ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.
Tawanda Gumbo - One of the best experts on this subject based on the ideXlab platform.
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nouveau short course therapy and morphism mapping for clinical pulmonary mycobacterium kansasii
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Shashikant Srivastava, Jannyuan Wang, Gesham Magombedze, Moti L Chapagain, Hungling Huang, Devyani Deshpande, Scott K Heysell, Jotam G Pasipanodya, Tawanda GumboAbstract:Standard therapy [isoniazid, rifampin, Ethambutol], with or without a macrolide, for pulmonary Mycobacterium kansasii lasts more than a year. Therefore, shorter treatment duration regimens are required. We used data from 32 Taiwanese patients treated with standard therapy who were followed using repetitive sampling-based sputum Mkn time-to-positivity in liquid cultures to calculate kill slopes [γ] based on ordinary differential equations and time-to-extinction of each patient's bacterial burden. The γ was 0.18 [95% Confidence Interval (CI): 0.16-0.20] log10 CFU/mL/day on standard therapy. Next, we identified Mkn time-to-extinction in the hollow fiber system model of pulmonary M. kansasii disease [HFS-Mkn] treated with standard therapy, which was a γ of 0.60 [95% CI: 0.45-0.69) log10 CFU/mL/day. The γs and time-to-extinctions between the two datasets formed structure-preserving maps based on category theory: thus, we could map them from one to the other using morphisms. This mapping identified a multistep non-linear transformation-factor for time-to-extinction from HFS-Mkn to patients. Next, a head-to-head study in the HFS-Mkn identified median time-to-extinction for standard therapy of 38.7 [95% CI: 29.1-53.2) days, isoniazid-rifampin-Ethambutol-moxifloxacin of 21.7 [95% CI: 19.1-25) days, isoniazid-rifampin-moxifloxacin of 22 [96% CI: 20.1-24.5) days, and rifampin-moxifloxacin-tedizolid of 20.7 [95% CI:18.5-29) days. Our transformation-factor based translation predicted the proportion of patients of 90.7 [88.74-92.35)% achieving cure with standard therapy at 12 months, and 6-months cure rates of 99.8 [95% CI: 99.27-99.95)% for isoniazid-rifampin-Ethambutol-moxifloxacin, 92.2 [90.37-93.71)% for isoniazid-rifampin-moxifloxacin, and 99.9 [99.44-99.99)% for rifampin-moxifloxacin-tedizolid. Thus, rifampin-moxifloxacin-tedizolid and isoniazid-rifampin-Ethambutol-moxifloxacin are predicted to be short-course chemotherapy regimens for pulmonary M. kansasii disease.
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optimizing Ethambutol dosing among hiv tuberculosis co infected patients a population pharmacokinetic modelling and simulation study
Journal of Antimicrobial Chemotherapy, 2019Co-Authors: Krina Mehta, Shashikant Srivastava, Jotam G Pasipanodya, Tawanda Gumbo, Shruthi Ravimohan, Chawangwa Modongo, Nicola M Zetola, Drew Weissman, Vijay Ivaturi, Gregory P BissonAbstract:Background Reduced Ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure. Objectives To perform a population pharmacokinetic study of Ethambutol in HIV/TB patients, and to evaluate an intensified Ethambutol weight-based dosing strategy to support pharmacokinetic target attainment. Methods We conducted a prospective study of Ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of Ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based Ethambutol dosing strategies. Results We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary Ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation. Conclusions Low serum Ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of Ethambutol increased following ART initiation. Supplementary Ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.
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Ethambutol pharmacokinetic variability is linked to body mass in overweight obese and extremely obese people
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Richard D Leff, Claudia Meek, Ronald G Hall, Mark A Swancutt, Tawanda GumboAbstract:We conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of 40 kg/m2, who received a single oral dose of 1,600 mg Ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6)3/4 and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized Ethambutol dosing regimens need to be designed for obese and extremely obese patients.
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Ethambutol optimal clinical dose and susceptibility breakpoint identification by use of a novel pharmacokinetic pharmacodynamic model of disseminated intracellular mycobacterium avium
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Devyani Deshpande, Shashikant Srivastava, Claudia Meek, Richard D Leff, Tawanda GumboAbstract:Ethambutol, together with a macrolide, is the backbone for treatment of disseminated Mycobacterium avium disease. However, at the standard dose of 15 mg/kg of body weight/day, Ethambutol efficacy is limited. In addition, susceptibility breakpoints have consistently failed to predict clinical outcome. We performed dose-effect studies with extracellular M. avium as well as with bacilli within human macrophages. The maximal kill rate (E(max)) for Ethambutol against extracellular bacilli was 5.54 log(10) CFU/ml, compared to 0.67 log(10) CFU/ml for intracellular M. avium, after 7 days of exposure. Thus, extracellular assays demonstrated high efficacy. We created a hollow-fiber system model of intracellular M. avium and performed microbial pharmacokinetic-pharmacodynamic studies using pharmacokinetics similar to those of Ethambutol for humans. The E(max) in the systems was 0.79 log(10) CFU/ml with 7 days of daily therapy, so the kill rates approximated those encountered in patients treated with Ethambutol monotherapy. Ratio of peak concentration to MIC (C(max)/MIC) was linked to microbial kill rate. The C(max)/MIC ratio needed to achieve the 90% effective concentration (EC(90)) in serum was 1.23, with a calculated intramacrophage C(max)/MIC ratio of 13. In 10,000 patient Monte Carlo simulations, doses of 15, 50, and 75 mg/kg achieved the EC(90) in 35.50%, 76.81%, and 86.12% of patients, respectively. Therefore, Ethambutol doses of >or=50 mg/kg twice a week would be predicted to be better than current doses of 15 mg/kg for treatment of disseminated M. avium disease. New susceptibility breakpoints and critical concentrations of 1 to 2 mg/liter were identified for the determination of Ethambutol-resistant M. avium in Middlebrook broth. Given that the modal MIC of clinical isolates is around 2 mg/liter, most isolates should be considered Ethambutol resistant.
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efflux pump derived multiple drug resistance to Ethambutol monotherapy in mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of Ethambutol
The Journal of Infectious Diseases, 2010Co-Authors: Shashikant Srivastava, Claudia Meek, Richard D Leff, Sandirai Musuka, Carleton Sherman, Tawanda GumboAbstract:Background In the treatment of tuberculosis, Ethambutol is used in case there is isoniazid resistance. We examined for the emergence of drug resistance to Ethambutol monotherapy in pharmacokinetic-pharmacodynamic studies in the hollow fiber system.
Janstefan Van Der Walt - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of Ethambutol in south african tuberculosis patients
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Siv Jonsson, Ulrika S. H. Simonsson, Alistair Davidse, Justin J Wilkins, Janstefan Van Der Walt, Mats O Karlsson, Pete Smith, Helen McilleronAbstract:Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of Ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with Ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of Ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to Ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of Ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.
Justin J Wilkins - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of Ethambutol in south african tuberculosis patients
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Siv Jonsson, Ulrika S. H. Simonsson, Alistair Davidse, Justin J Wilkins, Janstefan Van Der Walt, Mats O Karlsson, Pete Smith, Helen McilleronAbstract:Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of Ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with Ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of Ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to Ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of Ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.
Rita Sood - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of visual function for early detection of Ethambutol toxicity
British Journal of Ophthalmology, 2009Co-Authors: Vimla Menon, Deepak Jain, Rohit Saxena, Rita SoodAbstract:Aim: The aim of the study was to evaluate various visual parameters for early detection of Ethambutol toxicity. Method: This was a prospective study of 104 eyes of 52 patients being treated with Ethambutol in the Directly Observed Treatment Strategy Centre (Dr R P Centre for Opthalmic Sciences, New Delhi, India). Visual acuity, visual fields, visual evoked responses (VER), stereoacuity and retinal nerve fibre layer (RNFL) thickness on optical coherence tomography (OCT) were assessed. Examinations were done before the start of therapy, after 1 and 2 months of treatment, and 1 month after stopping Ethambutol. Results: No visual functional defect was noted at baseline. On follow-up, visual acuity, colour vision, contrast sensitivity, fundus and stereoacuity were not affected in any patient. Visual field defects developed in 7.69% (8/104) of the eyes. Pattern-VER showed an increased mean latency of the P 100 wave after 1 and 2 months of therapy (p Conclusion: Pattern-VER and visual field examinations are sensitive tests to detect early toxicity. Together with OCT, they may help to identify patients who are likely to develop clinical toxicity.