scholarly journals Cumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01207-20 ◽  
Author(s):  
Suresh Mallikaarjun ◽  
Moti L. Chapagain ◽  
Tomohiro Sasaki ◽  
Norimitsu Hariguchi ◽  
Devyani Deshpande ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
System Model ◽  
Qtc Interval ◽  
Fiber System ◽  
Time Curve ◽  
Once Daily ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Concentration Time ◽  
Mdr Tb

ABSTRACTPharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0–24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0–24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0–24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0–24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia’s formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.

scholarly journals Amikacin Optimal Exposure Targets in the Hollow-Fiber System Model of Tuberculosis

2016 ◽  
Vol 60 (10) ◽  
pp. 5922-5927 ◽  
Author(s):  
Shashikant Srivastava ◽  
Chawanga Modongo ◽  
Chandima W. Siyambalapitiyage Dona ◽  
Jotam G. Pasipanodya ◽  
Devyani Deshpande ◽  
...  
Keyword(s):  
Hollow Fiber ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
System Model ◽  
Intermittent Therapy ◽  
Fiber System ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Mdr Tb

ABSTRACTAminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). However, formal pharmacokinetic/pharmacodynamic (PK/PD) studies to identify amikacin exposures and dosing schedules that optimizeMycobacterium tuberculosiskilling have not been performed. It is believed that aminoglycosides do not work well under acidic conditions, which, if true, would mean poor sterilizing activity against semidormant bacilli at low pH. We performed time-kill studies to compare the bactericidal effect of amikacin in log-phase-growth bacilli with the sterilizing effect in semidormant bacilli at pH 5.8 in broth. In log-phaseM. tuberculosisat normal pH versus semidormantM. tuberculosisat pH 5.8, the maximal kill (Emax) estimate and 95% confidence interval (CI) were 5.39 (95% CI, 4.91 to 5.63) versus 4.88 (CI, 4.46 to 5.22) log10CFU/ml, while the concentration mediating 50% ofEmax(EC50) was 1.0 (CI, 0. 0.86 to 1.12) versus 0.60 (CI, 0.50 to 0.66) times the MIC, respectively. Thus, the optimal exposures and kill rates identified for log-phaseM. tuberculosiswill be optimal even for semidormant bacilli. Next, we performed exposure-response and dose-scheduling studies in the hollow-fiber system model of tuberculosis using log-phaseM. tuberculosis. We recapitulated the amikacin concentration-time profiles observed in lungs of patients treated over 28 days. The PK/PD index linked toM. tuberculosiskill was the peak concentration (Cmax)-to-MIC ratio (r2> 0.99), closely followed by the area under the concentration-time curve from 0 to 24 h (AUC0–24)-to-MIC ratio (r2= 0.98). The EC90was aCmax/MIC ratio of 10.13 (95% CI, 7.73 to 12.48). The EC90is the dosing target for intermittent therapy that optimizes cure in TB programs for MDR-TB patients.

scholarly journals Pharmacokinetics of Second-Line Antituberculosis Drugs in Children with Multidrug-Resistant Tuberculosis in India

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Agibothu Kupparam Hemanth Kumar ◽  
Alok Kumar ◽  
Thiruvengadam Kannan ◽  
Rakesh Bhatia ◽  
Dipti Agarwal ◽  
...  
Keyword(s):  
High Performance ◽  
Linear Regression Analysis ◽  
Multidrug Resistant ◽  
Control Programme ◽  
Second Line ◽  
Time Curve ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
The Government

ABSTRACTWe studied the pharmacokinetics of levofloxacin (LFX), pyrazinamide (PZA), ethionamide (ETH), and cycloserine (CS) in children with multidrug-resistant tuberculosis (MDR-TB) who were being treated according to the Revised National TB Control Programme (RNTCP) guidelines in India. This observational, pharmacokinetic study was conducted in 25 children with MDR-TB at the Sarojini Naidu Medical College, Agra, India, who were being treated with a 24-month daily regimen. Serial blood samples were collected after directly observed administration of drugs. Estimations of plasma LFX, PZA, ETH, and CS were undertaken according to validated methods by high-performance liquid chromatography. Adverse events were noted at 6 months of treatment. The peak concentration (Cmax) of LFX was significantly higher in female than male children (11.5 μg/ml versus 7.3 μg/ml;P= 0.017). Children below 12 years of age had significantly higher ETH exposure (area under the concentration-time curve from 0 to 8 h [AUC0–8]) than those above 12 years of age (17.5 μg/ml · h versus 9.4 μg/ml;P= 0.030). Multiple linear regression analysis showed significant influence of gender onCmaxof ETH and age onCmaxand AUC0–8of CS. This is the first and only study from India reporting on the pharmacokinetics of LFX, ETH, PZA, and CS in children with MDR-TB treated in the Government of India program. More studies on the safety and pharmacokinetics of second-line anti-TB drugs in children with MDR-TB from different settings are required.

scholarly journals Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients

2016 ◽  
Vol 60 (10) ◽  
pp. 5928-5932 ◽  
Author(s):  
Chawangwa Modongo ◽  
Jotam G. Pasipanodya ◽  
Beki T. Magazi ◽  
Shashikant Srivastava ◽  
Nicola M. Zetola ◽  
...  
Keyword(s):  
Characteristic Curve ◽  
Multidrug Resistant ◽  
Sputum Culture ◽  
Classification And Regression Tree ◽  
Fiber System ◽  
Sputum Culture Conversion ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Culture Conversion

ABSTRACTAminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0–24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0–24, and trough concentrations. The primary node for failure had two competing variables,Cmaxof <67 mg/liter and AUC0–24of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R2= 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacinCmaxof ≥67 mg/liter versus 3/15 (20%) in those with aCmaxof <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacinCmaxand AUC0–24below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.

scholarly journals Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Charles A. Peloquin ◽  
Patrick P. J. Phillips ◽  
Carole D. Mitnick ◽  
Kathleen Eisenach ◽  
Ramonde F. Patientia ◽  
...  
Keyword(s):  
South Africa ◽  
Multidrug Resistant ◽  
Maximum Plasma ◽  
Second Line ◽  
Time Curve ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Concentration Time ◽  
Nominal Dose ◽  
Median Maximum

ABSTRACTPatients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0−24) were 109.49, 97.86, 145.33, and 207.04 μg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 μg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.)

scholarly journals Evaluation of Saliva as a Potential Alternative Sampling Matrix for Therapeutic Drug Monitoring of Levofloxacin in Patients with Multidrug-Resistant Tuberculosis

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Samiksha Ghimire ◽  
Bhagwan Maharjan ◽  
Erwin M. Jongedijk ◽  
Jos G. W. Kosterink ◽  
Gokarna R. Ghimire ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Multidrug Resistant ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Time Curve ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Liquid Chromatography Tandem Mass ◽  
Mdr Tb

ABSTRACT Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multidrug-resistant tuberculosis (MDR-TB) patients. The objectives of this study were (i) to evaluate the correlation between plasma and salivary levofloxacin (Lfx) concentrations in MDR-TB patients and (ii) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in areas where TB is endemic. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (750- to 1,000-mg once-daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental kinetics. Lfx drug exposures were evaluated in 23 MDR-TB patients. During the first month, the median (interquartile range [IQR]) areas under the concentration-time curve from 0 to 24 h (AUC0–24) were 67.09 (53.93 to 98.37) mg ⋅ h/liter in saliva and 99.91 (76.80 to 129.70) mg ⋅ h/liter in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53 to 0.99). Similarly, during the second month, the median (IQR) AUC0–24 were 75.63 (61.45 to 125.5) mg ⋅ h/liter in saliva and 102.7 (84.46 to 131.9) mg ⋅ h/liter in plasma, with an S/P ratio of 0.73 (0.66 to 1.18). Furthermore, large inter- and intraindividual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semiquantitatively predicting Lfx plasma levels. (This study has been registered at ClinicalTrials.gov under identifier NCT03000517.)

scholarly journals Gatifloxacin Pharmacokinetics/Pharmacodynamics–based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis

2018 ◽  
Vol 67 (suppl_3) ◽  
pp. S274-S283 ◽  
Author(s):  
Devyani Deshpande ◽  
Jotam G Pasipanodya ◽  
Shashikant Srivastava ◽  
Paula Bendet ◽  
Thearith Koeuth ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Data ◽  
Multidrug Resistant ◽  
Classification And Regression Tree ◽  
Fiber System ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Target Exposure ◽  
Mdr Tb ◽  
Meningeal Tuberculosis

Abstract Background Gatifloxacin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB). The optimal dose is unknown. Methods We performed a 28-day gatifloxacin hollow-fiber system model of tuberculosis (HFS-TB) study in order to identify the target exposures associated with optimal kill rates and resistance suppression. Monte Carlo experiments (MCE) were used to identify the dose that would achieve the target exposure in 10000 adult patients with meningeal or pulmonary MDR-TB. The optimal doses identified were validated using probit analyses of clinical data from 2 prospective clinical trials of patients with pulmonary and meningeal tuberculosis. Classification and regression-tree (CART) analyses were used to identify the gatifloxacin minimum inhibitory concentration (MIC) below which patients failed or relapsed on combination therapy. Results The target exposure associated with optimal microbial kill rates and resistance suppression in the HFS-TB was a 0–24 hour area under the concentration-time curve-to-MIC of 184. MCE identified an optimal gatifloxacin dose of 800 mg/day for pulmonary and 1200 mg/day for meningeal MDR-TB, and a clinical susceptibility breakpoint of MIC ≤ 0.5 mg/L. In clinical trials, CART identified that 79% patients failed therapy if MIC was &gt;2 mg/L, but 98% were cured if MIC was ≤0.5 mg/L. Probit analysis of clinical data demonstrated a &gt;90% probability of a cure in patients if treated with 800 mg/day for pulmonary tuberculosis and 1200 mg/day for meningeal tuberculosis. Doses ≤400 mg/day were suboptimal. Conclusions Gatifloxacin doses of 800 mg/day and 1200 mg/day are recommended for pulmonary and meningeal MDR-TB treatment, respectively. Gatifloxacin has a susceptible dose-dependent zone at MICs 0.5–2 mg/L.

scholarly journals The epidemiologic impact and cost-effectiveness of new tuberculosis vaccines on multidrug-resistant tuberculosis in India and China

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chathika K Weerasuriya ◽  
Rebecca C Harris ◽  
C Finn McQuaid ◽  
Fiammetta Bozzani ◽  
Yunzhou Ruan ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Cost Effective ◽  
Multidrug Resistant ◽  
Second Line ◽  
Second Line Therapy ◽  
China And India ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Line Therapy ◽  
Mdr Tb

Abstract Background Despite recent advances through the development pipeline, how novel tuberculosis (TB) vaccines might affect rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is unknown. We investigated the epidemiologic impact, cost-effectiveness, and budget impact of hypothetical novel prophylactic prevention of disease TB vaccines on RR/MDR-TB in China and India. Methods We constructed a deterministic, compartmental, age-, drug-resistance- and treatment history-stratified dynamic transmission model of tuberculosis. We introduced novel vaccines from 2027, with post- (PSI) or both pre- and post-infection (P&PI) efficacy, conferring 10 years of protection, with 50% efficacy. We measured vaccine cost-effectiveness over 2027–2050 as USD/DALY averted-against 1-times GDP/capita, and two healthcare opportunity cost-based (HCOC), thresholds. We carried out scenario analyses. Results By 2050, the P&PI vaccine reduced RR/MDR-TB incidence rate by 71% (UI: 69–72) and 72% (UI: 70–74), and the PSI vaccine by 31% (UI: 30–32) and 44% (UI: 42–47) in China and India, respectively. In India, we found both USD 10 P&PI and PSI vaccines cost-effective at the 1-times GDP and upper HCOC thresholds and P&PI vaccines cost-effective at the lower HCOC threshold. In China, both vaccines were cost-effective at the 1-times GDP threshold. P&PI vaccine remained cost-effective at the lower HCOC threshold with 49% probability and PSI vaccines at the upper HCOC threshold with 21% probability. The P&PI vaccine was predicted to avert 0.9 million (UI: 0.8–1.1) and 1.1 million (UI: 0.9–1.4) second-line therapy regimens in China and India between 2027 and 2050, respectively. Conclusions Novel TB vaccination is likely to substantially reduce the future burden of RR/MDR-TB, while averting the need for second-line therapy. Vaccination may be cost-effective depending on vaccine characteristics and setting.

PP581 Catastrophic Costs Of Multidrug-Resistant Tuberculosis: Estimation Based On The Cost Of Treatment In China

2020 ◽  
Vol 36 (S1) ◽  
pp. 43-43
Author(s):  
Lijun Shen ◽  
Shangshang Gu ◽  
Fan Zhang ◽  
Zhao Liu ◽  
Yuehua Liu
Keyword(s):  
Market Price ◽  
Multidrug Resistant ◽  
Policy Support ◽  
World Health ◽  
Chinese Patients ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Drug Affordability ◽  
The Cost

IntroductionChina bears a considerably high burden of multidrug-resistant tuberculosis (MDR-TB). Second-line anti-TB drugs are urgently needed yet domestic MDR-TB drugs are expensive and lack policy support. Patients’ living conditions are closely related to the drug affordability. The national TB prevention programs should play a critical role. The purpose of this study is to measure the cost of treating MDR-TB patients under different treatment schemes and price sources. The results of this study are expected to inform the relevant drug protection policies and provide inputs for further cost-effectiveness analyses.MethodsBased on the treatment plan of China's Multidrug-Resistant Pulmonary Tuberculosis Clinical Path (2012 edition) and the World Health Organization (WHO) Drug-Resistant Tuberculosis Treatment Guide (2018 edition), the treatment costs of MDR-TB were measured under different scenarios. Catastrophic health expenditure was then calculated if the treatment cost exceeds 40 percent of the household's non-subsistence income. National, rural and disposable income per capita in 2018, were used to represent Chinese patients’ affordability.ResultsUnder varied treatment schemes and market price sources in China, the total costs for MDR-TB patients range from 19,401 to 126,703 CNY [2,853 to 18,633 USD] per person. Under current prices, all treatment schemes recommended by the WHO will incur catastrophic costs for Chinese MDR-TB patients. Significant differences were found between rural and urban areas as 52.8 percent of the treatment listed in the 2012 China Guideline would lead to catastrophic cost for rural patients but not urban ones.ConclusionsOur study concludes that the domestic drugs are more expensive than the international purchase price and the treatment of MDR-TB imposes substantial economic burden on patients, especially in the rural areas. The results of the study also indicate that it is urgent for the state to emphasize government responsibility and initiate centralized procurement for price negotiations to reduce the market price of MDR-TB drugs. The urban-rural gap should also be addressed in the design of future policies to ensure the drug affordability for all patients in need.

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