A5035677363- Peptidase Inhibition and Analysis
- Neuroendocrine Tumor Research Advances
- Mathematical Biology Tumor Growth
- Pancreatic and Hepatic Oncology Research
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Lung Cancer Research Studies
- Cancer Research and Treatments
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Cancer Cells and Metastasis
- Angiogenesis and VEGF in Cancer
- DNA Repair Mechanisms
- Radiopharmaceutical Chemistry and Applications
- Neuropeptides and Animal Physiology
- Nanoplatforms for cancer theranostics
- Adenosine and Purinergic Signaling
- Radiation Therapy and Dosimetry
- PARP inhibition in cancer therapy
- Effects of Radiation Exposure
- Histone Deacetylase Inhibitors Research
- Kruppel-like factors research
- Pharmacological Effects and Toxicity Studies
- Malaria Research and Control
Merck (Germany)
2019-2025
Simcyp (United Kingdom)
2020
Medicines for Malaria Venture
2020
Roche (Switzerland)
2015-2016
Institut national de recherche en informatique et en automatique
2012
Unité de Mathématiques Pures et Appliquées
2012
Centre National de la Recherche Scientifique
2012
École Normale Supérieure de Lyon
2012
Université Claude Bernard Lyon 1
2012
Abstract Background Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework address those challenges. Methods A semi-mechanistic pharmacokinetic-pharmacodynamic model tumour growth inhibition was developed investigate efficacy PARP and ATR inhibitors monotherapies, combination. Key features DNA damage response were incorporated into allow emergence synthetic...
Methionine aminopeptidase 2 (MetAP2) is essential to endothelial cell growth and proliferation during tumor angiogenesis. M8891 a novel orally bioavailable, potent, selective, reversible MetAP2 inhibitor with antiangiogenic antitumor activity in preclinical studies. The safety, tolerability, pharmacokinetics, pharmacodynamics of monotherapy were assessed phase I, first-in-human, multicenter, open-label, single-arm, dose-escalation study (NCT03138538). Patients advanced solid tumors received...
Radiation therapy, whether given alone or in combination with chemical agents, is one of the cornerstones oncology. We develop a quantitative model that describes tumor growth during and after treatment radiation radiosensitizing agents. The also long-term effects including regrowth eradication. challenge data from xenograft study using clinically relevant administration schedule use mixed-effects approach for model-fitting. calibrated to predict exposure combinations result eradication...
M5717 is a novel drug inhibiting synthesis of elongation factor 2 (PeEF2) in Plasmodium species, showing potent anti-malarial activity preclinical studies. Traditional daily-dosing animal experiments estimating maximum safe starting dose for first-in-human study ('no observed adverse effect level'; NOAEL) were unsuccessful due to the long pharmacokinetic half-life M5717, causing significant accumulation and high exposure. This describes an innovative strategy produce GLP-certified toxicology...
The active enantiomer R-Praziquantel (PZQ) shows a clinically lower relative exposure when administered enantiomerically pure compared with racemic form. We investigated the hypothesis that enantiomer-enantiomer interactions on cytochrome P450 (P450) enzymes could explain this observation and aimed to further deepen understanding of PZQ metabolism. First, in an vitro metabolite profiling study, formation multiple metabolites per P450, together observed interconversion cis-4'-OH-PZQ...
Abstract Purpose Tumor growth inhibition (TGI) models are regularly used to quantify the PK–PD relationship between drug concentration and in vivo efficacy oncology. These typically calibrated with data from xenograft mice before being for clinical predictions, translational methods have be applied. Currently, such commonly based on replacing model components or scaling of parameters. However, difficulties remain how accurately account inter-species differences. Therefore, more research must...
M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, <i>β</i>5i, PSMB8) proteolytic subunit immunoproteasome, a component cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe fit-for-purpose pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy modeling based on preclinical data from several species. The inhibition LMP7 activity (PD) and tumor...
Abstract Introduction M8891 is a selective and reversible inhibitor of methionine aminopeptidase 2 (MetAP2). We describe translational research to define the target pharmacokinetics (PK) associated pharmacodynamic (PD) levels, which were used support efficacious dose selection in humans. Methods In vitro vivo PK characteristics investigated animal species, data integrated using vitro–in correlation allometric methods predict clearance, volume distribution, absorption parameters parallel,...
The vascular endothelial growth factor (VEGF) is known as one of the main promoter angiogenesis - process blood vessel formation. Angiogenesis has been recognized a key stage for cancer development and metastasis. In this paper, we propose structural model molecular pathways involved in cells response to VEGF stimuli. model, built on qualitative information from knowledge databases, composed 38 ordinary differential equations with 78 parameters focuses signalling driving cell proliferation,...
A central question in drug discovery is how to select candidates from a large number of available compounds. This analysis presents model-based approach for comparing and ranking combinations radiation radiosensitizers. The quantitative based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations radiosensitizers are evaluated their ability induce tumor regression relative toxicity other potential costs. presented form case study where objective find most promising...
Abstract Background To increase the chances of finding efficacious anticancer drugs, improve development times and reduce costs, it is interest to rank test compounds based on their potential for human use as early possible in drug process. In this paper, we present a method ranking radiosensitizers using preclinical data. Methods We used data from three xenograft mice studies calibrate model that accounts radiation treatment combined with radiosensitizers. A nonlinear mixed effects approach...
<p>TEAEs occurring in ≥15% of patients overall by dose level</p>
<p>Met-EF1α/protein levels in tumor on cycle 2, day 1 (individual patient dot plot). Open symbols show the pretreatment Met-EF1α levels, and corresponding closed for individual patients doses of 7, 12, 20, 35, 60, 80 mg. The dashed line shows target level 125 μg/mg protein expected to be correlated with efficacy. Met-EF1α, methionylated elongation factor 1α.</p>
<p>Plasma concentration–time profiles of M8891 (mean ± SD) at cycle 1, day 1 (<b>A</b>) and 15 (<b>B</b>). The dashed line shows the target C<sub>trough</sub> level 1,500 ng/mL expected to be correlated with efficacy. QD, once daily.</p>
<p>Pharmacokinetic parameters of M8891 in plasma by treatment after single (cycle 1, day 1) and multiple dosing 15)</p>
<p>Patient demographics and disposition</p>
<p>Overview of TEAEs for M8891</p>
<p>Met-EF1α/protein levels in tumor on cycle 2, day 1 (individual patient dot plot). Open symbols show the pretreatment Met-EF1α levels, and corresponding closed for individual patients doses of 7, 12, 20, 35, 60, 80 mg. The dashed line shows target level 125 μg/mg protein expected to be correlated with efficacy. Met-EF1α, methionylated elongation factor 1α.</p>
<p>Patient demographics and disposition</p>
<div><p>Methionine aminopeptidase 2 (MetAP2) is essential to endothelial cell growth and proliferation during tumor angiogenesis. M8891 a novel orally bioavailable, potent, selective, reversible MetAP2 inhibitor with antiangiogenic antitumor activity in preclinical studies. The safety, tolerability, pharmacokinetics, pharmacodynamics of monotherapy were assessed phase I, first-in-human, multicenter, open-label, single-arm, dose-escalation study (NCT03138538). Patients advanced...