Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions

Ordoñez, Alvaro A.; Wang, Hechuan; Magombedze, Gesham; Ruiz-Bedoya, Camilo A.; Srivastava, Shashikant; Chen, Allen; Tucker, Elizabeth W.; Urbanowski, Michael E.; Pieterse, Lisa; Cardozo, E. Fabián; Lodge, Martin A.; Shah, Maunank; Holt, Daniel P.; Mathews, William B.; Dannals, Robert F.; Gobburu, Jogarao; Peloquin, Charles A.; Rowe, Steven P.; Gumbo, Tawanda; Ivaturi, Vijay; Jain, Sanjay

doi:10.1038/s41591-020-0770-2

Cited by 98 publications

(134 citation statements)

References 43 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…Another common misconception about phase 0 and especially microdosing is that since subtherapeutic exposures are being used, no pharmacodynamic, biomarker or MOA data can be obtained. However, even exposures that do not lead to system-level macroscopic effects (that the guidelines identify as 'pharmacologically active' such as therapeutic or tolerability-related effects) can still engage in pharmacological dynamics and provide information on the so-called pillars of drug development decision-making: target compartment/ tissue disposition, binding to receptors relevant to the MOA and postreceptor modulation 33,70,94,189 . Numerous examples are available from research into the methodology of phase 0 as well as from phase 0 applications in novel drug development (Table 3).…”

Section: Pd Biomarker And/or Moa Datamentioning

confidence: 99%

Phase 0/microdosing approaches: time for mainstream application in drug development?

Burt¹,

Young

Lee

et al. 2020

Nat Rev Drug Discov

View full text Add to dashboard Cite

Phase 0 approaches-which include microdosing-evaluate subtherapeutic exposures of new drugs in first-inhuman studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios.

show abstract

Section: Pd Biomarker And/or Moa Datamentioning

confidence: 99%

Phase 0/microdosing approaches: time for mainstream application in drug development?

Burt¹,

Young

Lee

et al. 2020

Nat Rev Drug Discov

View full text Add to dashboard Cite

show abstract

“…Toxic effects of FQs on humans have been attributed to their interactions with different receptor complexes, such as the blockade of the GABAa receptor complex within the central nervous system, leading to excitotoxic type effects and oxidative stress [14]. These toxic effects, however, are unlikely to be noted at a tracer dose that is used for PET/SPECT imaging because of the relatively high IC50 of FQs with respect to the micromolar quantities injected as radiopharmaceuticals.…”

Section: The Role Of Pathogenic Bacteria In Infections and Bacteria-smentioning

confidence: 99%

“…Infectious lesions are characterized by a heterogeneous microenvironment which may include spatial physical and chemical differences as well as varied immune responses. These non-specific radiotracers targeted at these microenvironment biomarkers may provide valuable information regarding the heterogeneity of infection sites and have the potential to inform on the efficacy of antimicrobial treatments [14,15] as well as host-directed therapies [13,16,17]. Hopefully in the future we will have many radiopharmaceuticals available, tailored for specific pathogens, and clinical conditions, thus having the maximum specificity (see Table 1).…”

Section: The Role Of Pathogenic Bacteria In Infections and Bacteria-smentioning

confidence: 99%

Imaging Bacteria with Radiolabelled Probes: Is It Feasible?

Artiko

Conserva

Ferro-Flores

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

Bacterial infections are the main cause of patient morbidity and mortality worldwide. Diagnosis can be difficult and delayed as well as the identification of the etiological pathogen, necessary for a tailored antibiotic therapy. Several non-invasive diagnostic procedures are available, all with pros and cons. Molecular nuclear medicine has highly contributed in this field by proposing several different radiopharmaceuticals (antimicrobial peptides, leukocytes, cytokines, antibiotics, sugars, etc.) but none proved to be highly specific for bacteria, although many agents in development look promising. Indeed, factors including the number and strain of bacteria, the infection site, and the host condition, may affect the specificity of the tested radiopharmaceuticals. At the Third European Congress on Infection/Inflammation Imaging, a round table discussion was dedicated to debate the pros and cons of different radiopharmaceuticals for imaging bacteria with the final goal to find a consensus on the most relevant research steps that should be fulfilled when testing a new probe, based on experience and cumulative published evidence.

show abstract

“…In general, non-invasive imaging of lesion pathology by computed tomography (CT) and positron emission tomography (PET) has the potential to improve the comparison between preclinical and clinical measurements of disease progression and treatment [102]. Ordonez et al have demonstrated this by using dynamic [ 11 C]rifampicin PET-CT imaging in patients newly diagnosed with pulmonary TB and rabbits infected with cavitary TB to noninvasively measure intralesional drug concentration-time profiles and, consequently, time to bacterial extinction [110]. They also employed integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments to predict the rifampicin dose required to achieve a cure in 4 months, which has a huge potential in antimicrobial drug development to shorten TB treatments [110].…”

Section: Prediction Of Human Pharmacokinetic-pharmacodynamic Relationmentioning

confidence: 99%

“…Ordonez et al have demonstrated this by using dynamic [ 11 C]rifampicin PET-CT imaging in patients newly diagnosed with pulmonary TB and rabbits infected with cavitary TB to noninvasively measure intralesional drug concentration-time profiles and, consequently, time to bacterial extinction [110]. They also employed integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments to predict the rifampicin dose required to achieve a cure in 4 months, which has a huge potential in antimicrobial drug development to shorten TB treatments [110]. It is clear that no single animal model represents a heterogeneous disease such as TB.…”

Section: Prediction Of Human Pharmacokinetic-pharmacodynamic Relationmentioning

confidence: 99%

Model-Informed Drug Discovery and Development Strategy for the Rapid Development of Anti-Tuberculosis Drug Combinations

et al. 2020

View full text Add to dashboard Cite

The increasing emergence of drug-resistant tuberculosis requires new effective and safe drug regimens. However, drug discovery and development are challenging, lengthy and costly. The framework of model-informed drug discovery and development (MID3) is proposed to be applied throughout the preclinical to clinical phases to provide an informative prediction of drug exposure and efficacy in humans in order to select novel anti-tuberculosis drug combinations. The MID3 includes pharmacokinetic-pharmacodynamic and quantitative systems pharmacology models, machine learning and artificial intelligence, which integrates all the available knowledge related to disease and the compounds. A translational in vitro-in vivo link throughout modeling and simulation is crucial to optimize the selection of regimens with the highest probability of receiving approval from regulatory authorities. In vitro-in vivo correlation (IVIVC) and physiologically-based pharmacokinetic modeling provide powerful tools to predict pharmacokinetic drug-drug interactions based on preclinical information. Mechanistic or semi-mechanistic pharmacokinetic-pharmacodynamic models have been successfully applied to predict the clinical exposure-response profile for anti-tuberculosis drugs using preclinical data. Potential pharmacodynamic drug-drug interactions can be predicted from in vitro data through IVIVC and pharmacokinetic-pharmacodynamic modeling accounting for translational factors. It is essential for academic and industrial drug developers to collaborate across disciplines to realize the huge potential of MID3.

show abstract

Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions

Cited by 98 publications

References 43 publications

Phase 0/microdosing approaches: time for mainstream application in drug development?

Phase 0/microdosing approaches: time for mainstream application in drug development?

Imaging Bacteria with Radiolabelled Probes: Is It Feasible?

Model-Informed Drug Discovery and Development Strategy for the Rapid Development of Anti-Tuberculosis Drug Combinations

Contact Info

Product

Resources

About