Dataset Information

A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations.

ABSTRACT: Background:Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development. Methods:In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The multistate TB pharmacometric (MTP) model was used to characterize the natural growth and exposure-response relationships of each drug after mono exposure. Pharmacodynamic interactions during combination exposure were characterized by linking the MTP model to the general pharmacodynamic interaction (GPDI) model with successful separation of the potential effect on each drug's potency (EC50) by the combining drug(s). Results:All combinations showed pharmacodynamic interactions at cfu level, where all combinations, except isoniazid plus ethambutol, showed more effect (synergy) than any of the drugs alone. Using preclinical information, the MTP-GPDI modelling approach was shown to correctly predict clinically observed pharmacodynamic interactions, as deviations from expected additivity. Conclusions:With the ability to predict clinical pharmacodynamic interactions, using preclinical information, the MTP-GPDI model approach outlined in this study constitutes groundwork for model-informed input to the development of new and enhancement of existing anti-TB combination regimens.

SUBMITTER: Clewe O

PROVIDER: S-EPMC5890720 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations.

Clewe Oskar O Wicha Sebastian G SG de Vogel Corné P CP de Steenwinkel Jurriaan E M JEM Simonsson Ulrika S H USH

The Journal of antimicrobial chemotherapy 20180201 2

<h4>Background</h4>Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development.<h4>Methods</h4>In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations ...[more]

PMID: 29136155

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Project description:The identification of drug/compound-target interactions (DTIs) constitutes the basis of drug discovery, for which computational predictive approaches have been developed. As a relatively new data-driven paradigm, proteochemometric (PCM) modeling utilizes both protein and compound properties as a pair at the input level and processes them via statistical/machine learning. The representation of input samples (i.e., proteins and their ligands) in the form of quantitative feature vectors is crucial for the extraction of interaction-related properties during the artificial learning and subsequent prediction of DTIs. Lately, the representation learning approach, in which input samples are automatically featurized via training and applying a machine/deep learning model, has been utilized in biomedical sciences. In this study, we performed a comprehensive investigation of different computational approaches/techniques for protein featurization (including both conventional approaches and the novel learned embeddings), data preparation and exploration, machine learning-based modeling, and performance evaluation with the aim of achieving better data representations and more successful learning in DTI prediction. For this, we first constructed realistic and challenging benchmark datasets on small, medium, and large scales to be used as reliable gold standards for specific DTI modeling tasks. We developed and applied a network analysis-based splitting strategy to divide datasets into structurally different training and test folds. Using these datasets together with various featurization methods, we trained and tested DTI prediction models and evaluated their performance from different angles. Our main findings can be summarized under 3 items: (i) random splitting of datasets into train and test folds leads to near-complete data memorization and produce highly over-optimistic results, as a result, should be avoided, (ii) learned protein sequence embeddings work well in DTI prediction and offer high potential, despite interaction-related properties (e.g., structures) of proteins are unused during their self-supervised model training, and (iii) during the learning process, PCM models tend to rely heavily on compound features while partially ignoring protein features, primarily due to the inherent bias in DTI data, indicating the requirement for new and unbiased datasets. We hope this study will aid researchers in designing robust and high-performing data-driven DTI prediction systems that have real-world translational value in drug discovery.

Dataset Information

A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations.

Publications

A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations.

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