Preclinical Development of Inhalable
            <scp>d</scp>
            -Cycloserine and Ethionamide To Overcome Pharmacokinetic Interaction and Enhance Efficacy against
            <i>Mycobacterium tuberculosis</i>

Ranjan, Rajeev; Srivastava, Ashish; Bharti, Reena; Roy, Trisha; Verma, Sonia; Ray, Lipika; Misra, Amit

doi:10.1128/aac.00099-19

Cited by 9 publications

(3 citation statements)

References 17 publications

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“…Ethionamide concentrations in patients with tuberculosis are generally lower than in healthy volunteers 10,12,13,15 . This difference can be attributed to possible pharmacokinetic interaction with other administered drugs, especially cycloserine, which has been shown in preclinical studies to cause a threefold decrease in ethionamide AUC 31 …”

Section: Discussionmentioning

confidence: 99%

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug‐resistant tuberculosis

Mugabo

Mulubwa

2021

Brit J Clinical Pharma

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Introduction Ethionamide is part of the drug‐resistant tuberculosis regimen whose pharmacokinetic (PK) and pharmacodynamic (PD) information is limited. The aim of the study was to describe the PK and simulate doses to assess PD attainment. Methods This was an observational population PK study of patients admitted for drug‐resistant tuberculosis at a hospital in South Africa. Nonlinear mixed‐effects modelling implemented in Monolix 2019R2 was used to estimate population pharmacokinetic parameters. We performed Monte Carlo simulations to assess and optimise the dose regimen. The target Cmax range was 2.5‐5 μg/mL, which is within the minimum inhibitory concentration (MIC) range. The target AUC0‐24h was 140.5 μg*h/mL, which corresponds to the PK/PD target ratio AUC0‐24h/MIC of 56.2. Results A one‐compartment pharmacokinetic model with a lag‐time, first‐order absorption and elimination best described the PK of ethionamide. The lag‐time, absorption rate constant (ka), volume of distribution (V/F) and clearance (Cl/F) were 0.66 hours, 0.434 h−1, 180 L and 99.5 L/h, respectively, for a typical individual weighing 52.6 kg. Between‐subject variability in lag‐time, ka, V/F and Cl/F were 38%, 92%, 168% and 120%, respectively. Simulation of the recommended doses of 15‐20 mg/kg, 500 mg, 750 mg and 1000 mg for patients in the weight bands <33, 33‐50, 51‐70 and >70 kg resulted in <17% and 3% of the patients achieving the target Cmax and AUC0‐24h, respectively. Conclusion There is high variability in ethionamide PK and very few patients attain the desired target exposure at standard or optimised doses. We propose individualised dose regimen optimisation.

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Section: Discussionmentioning

confidence: 99%

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug‐resistant tuberculosis

Mugabo

Mulubwa

2021

Brit J Clinical Pharma

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“…In conclusion, determination of ethionamide MIC before treatment is highly desirable, taking into account the inability to increase doses due to drug toxicity. Furthermore, a large individual variation of pK/pD parameters [ 36 ] and interaction with other drugs [ 35 , 44 ] require personalized treatment with therapeutic drug monitoring.…”

Section: Discussionmentioning

confidence: 99%

Molecular Determinants of Ethionamide Resistance in Clinical Isolates of Mycobacterium tuberculosis

Ushtanit

Kulagina

Mikhailova³

et al. 2022

Antibiotics

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Background: Ethionamide and prothionamide are now included in group C of the WHO recommended drugs for the treatment of tuberculosis resistant to rifampicin and multidrug-resistant tuberculosis. The clinical relevance of ethionamide and prothionamide has increased with the wide spread of resistant tuberculosis. Methods: We retrospectively analyzed 349 clinical isolates obtained between 2016 and 2020. The susceptibility to ethionamide was tested using both the BactecTM MGITTM 960 system and the SensititreTM MYCOTB plate. Results: The MIC of ethionamide increases with the total resistance of the isolates in a row from susceptible to XDR strains. A significant part of the isolates have a MIC below the breakpoint: 25%, 36%, and 50% for XDR, pre-XDR, and MDR strains. Sensitivity and specificity of detection of mutations were 96% and 86% using MGIT resistance as a reference. Conclusions: Phenotypic methods for testing ethionamide are imperfectly correlated, and the isolates with MIC of 5 mg/L have the intermediate resistance. A significant proportion of resistant TB cases are susceptible and eligible for ethionamide treatment. Resistance could be explained using only analysis of loci ethA, PfabG1, and inhA for most isolates in the Moscow region. The promoter mutation PfabG1 c(-15)t predicts resistance to ethionamide with high specificity but low sensitivity.

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“…Therefore, our results provide informed PK/PD support for the most recent guidelines, which suggest using other, more-potent drugs while deprioritizing ETA (2). Of interest, however, companion drugs consisting of inhalable ETA and a booster are being investigated for an improved antimycobacterial activity and toxicity profile, which could reintroduce ETA as a desirable agent for MDR-TB patients (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

Al‐Shaer

Märtson

Alghamdi

et al. 2020

Antimicrob Agents Chemother

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Ethionamide (ETA), an isonicotinic acid derivative, is part of multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines deprioritized ETA due to potential less effectiveness compared to other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens to assess target attainment. This study included subjects from four different sites, including both healthy volunteers and patients with MDR-TB. The TB centers included were two in the US and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, 1,000-2,250 mg total daily regimens were simulated, and target attainment using published minimum inhibitory concentrations (MICs) and 1.0-log kill and resistance suppression targets were assessed using Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag-time. The mean (SD) final population parameter estimates were: absorption rate constant 1.02 hr-1 (1.11), elimination rate constant 0.69 hr-1 (0.46), volume of distribution 104.16 L (59.87), and lag-time 0.43 hr (0.32). Total daily dose of 1,500 mg or more was needed to achieve ≥90% 1.0-log kill target attainment at MIC 1 mg/L, and 2,250 mg/day achieved 80% resistance suppression target attainment at MIC 0.5 mg/L. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting current recommendations for ETA deprioritization.

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Preclinical Development of Inhalable d -Cycloserine and Ethionamide To Overcome Pharmacokinetic Interaction and Enhance Efficacy against Mycobacterium tuberculosis

Cited by 9 publications

References 17 publications

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug‐resistant tuberculosis

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug‐resistant tuberculosis

Molecular Determinants of Ethionamide Resistance in Clinical Isolates of Mycobacterium tuberculosis

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

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