The implications of model-informed drug discovery and development for tuberculosis

Muliaditan, Morris; Davies, Geraint R.; Simonsson, Ulrika S. H.; Gillespie, Stephen H.; Pasqua, Oscar Della

doi:10.1016/j.drudis.2016.09.004

Cited by 15 publications

(10 citation statements)

References 29 publications

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“…The WHO and International Union Against Tuberculosis and Lung Disease (IUATLD) have published guidelines for treatment of tuberculosis (TB) which include recommendations for standardized first-line dosing regimens 1,2 . Although considerably effective in clinical trial settings, the rationale underpinning dosing regimens of modern short-course therapy have been empirical 3 . As a result, the dosing regimens that are currently used for TB treatment have never been optimized taking into account the known sources of variability in the pharmacokinetics (PK) of each drug.…”

Section: Introductionmentioning

confidence: 99%

How long will treatment guidelines for TB continue to overlook variability in drug exposure?

Muliaditan

Pasqua

2019

Journal of Antimicrobial Chemotherapy

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Background Despite wide clinical acceptance, the use of weight-banded dosing regimens for the treatment of TB in adults has been defined on an empirical basis. The potential impact of known covariate factors on exposure to different drugs has not been taken into account. Objectives To evaluate the effect of demographic factors on the exposure to standard of care drugs after weight-banded dosing, as currently recommended by TB treatment guidelines. In addition, we aim to identify alternative dosing regimens that ensure comparable systemic exposure across the overall patient population. Methods Clinical trial simulations were performed to assess the differences in systemic exposure in a cohort of virtual patients. Secondary pharmacokinetic parameters were used to evaluate the adequacy of each regimen along with the percentage of patients achieving predefined thresholds. Results Our results show that patients weighing less than 40 kg are underexposed relative to patients with higher body weight. The opposite trend was observed following a crude weight band-based dosing regimen with 50 kg as the cut-off point. Simulations indicate that a fixed-dose regimen based on three (<40 kg), four (40–70 kg) or five (>70 kg) tablets of 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide and 275 mg ethambutol reduces variability in exposure, increasing the overall probability of favourable long-term outcome across the population. Conclusions These findings suggest the need to revisit current guidelines for the dose of standard of care drugs for TB treatment in adults. The proposed fixed-dose regimen should be considered in future clinical trials.

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Section: Introductionmentioning

confidence: 99%

How long will treatment guidelines for TB continue to overlook variability in drug exposure?

Muliaditan

Pasqua

2019

Journal of Antimicrobial Chemotherapy

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“…PlatformTM was developed to support data management services for the eTRIKS platform. Throughout the eTRIKS project, we had the opportunity to gather requirements and learn about real problems drawn from many eTRIKS supported projects such as U-BIOPRED 19 , OncoTrack 20 , PreDiCT-TB 21 to cite a few. Here we present our proof-of-concept implementation drawn from one of the eTRIKS supported projects.…”

Section: Resultsmentioning

confidence: 99%

PlatformTM, a standards-based data custodianship platform for translational medicine research

et al. 2019

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Biomedical informatics has traditionally adopted a linear view of the informatics process (collect, store and analyse) in translational medicine (TM) studies; focusing primarily on the challenges in data integration and analysis. However, a data management challenge presents itself with the new lifecycle view of data emphasized by the recent calls for data re-use, long term data preservation, and data sharing. There is currently a lack of dedicated infrastructure focused on the ‘manageability’ of the data lifecycle in TM research between data collection and analysis. Current community efforts towards establishing a culture for open science prompt the creation of a data custodianship environment for management of TM data assets to support data reuse and reproducibility of research results. Here we present the development of a lifecycle-based methodology to create a metadata management framework based on community driven standards for standardisation, consolidation and integration of TM research data. Based on this framework, we also present the development of a new platform (PlatformTM) focused on managing the lifecycle for translational research data assets.

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“…Unfortunately, it provides limited information on the pharmacokinetics and pharmacodynamics of the drug (Dooley et al, 2019). The main cause of failures in the clinical development of drugs is its insufficient effectiveness, which is associated with an accurate determination of pharmacokinetics (Muliaditan et al, 2017). Before entering clinical trials, it is essential to gather much information about the exposure-response relationship and the relationship between pharmacokinetics and toxicity of the tested substance.…”

Section: Prospective Antitubercular Chemotherapymentioning

confidence: 99%

Early Drug Development and Evaluation of Putative Antitubercular Compounds in the -Omics Era

et al. 2021

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Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. According to the WHO, the disease is one of the top 10 causes of death of people worldwide. Mycobacterium tuberculosis is an intracellular pathogen with an unusually thick, waxy cell wall and a complex life cycle. These factors, combined with M. tuberculosis ability to enter prolonged periods of latency, make the bacterium very difficult to eradicate. The standard treatment of TB requires 6–20months, depending on the drug susceptibility of the infecting strain. The need to take cocktails of antibiotics to treat tuberculosis effectively and the emergence of drug-resistant strains prompts the need to search for new antitubercular compounds. This review provides a perspective on how modern -omic technologies facilitate the drug discovery process for tuberculosis treatment. We discuss how methods of DNA and RNA sequencing, proteomics, and genetic manipulation of organisms increase our understanding of mechanisms of action of antibiotics and allow the evaluation of drugs. We explore the utility of mathematical modeling and modern computational analysis for the drug discovery process. Finally, we summarize how -omic technologies contribute to our understanding of the emergence of drug resistance.

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The implications of model-informed drug discovery and development for tuberculosis

Cited by 15 publications

References 29 publications

How long will treatment guidelines for TB continue to overlook variability in drug exposure?

How long will treatment guidelines for TB continue to overlook variability in drug exposure?

PlatformTM, a standards-based data custodianship platform for translational medicine research

Early Drug Development and Evaluation of Putative Antitubercular Compounds in the -Omics Era

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