Hugues Chanteux

Hugues Chanteux
Union Chimique Belge (UCB) | UCB · QP-DMPK

Pharm, PhD

About

50
Publications
7,983
Reads
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1,805
Citations
Citations since 2017
15 Research Items
1021 Citations
2017201820192020202120222023050100150200
2017201820192020202120222023050100150200
2017201820192020202120222023050100150200
2017201820192020202120222023050100150200
Additional affiliations
October 2003 - September 2005
Université Catholique de Louvain - UCLouvain
Position
  • PhD
September 1999 - September 2003
Université Catholique de Louvain - UCLouvain
Position
  • PhD Student

Publications

Publications (50)
Article
Full-text available
The aim of the study was to identify the enzyme(s) involved in the hydrolysis of the ethyl ester prodrug CDP323, as well as to characterize its transesterification in the presence of ethanol with special emphasis on the risks of drug-drug interaction. The hydrolysis of CDP323 was evaluated in vitro using human liver and intestinal microsomes and re...
Article
Full-text available
1. A fast, straightforward and cost-effective assay was validated for the assessment of CYP induction in cryopreserved human hepatocytes cultured in 48-well plates. The cocktail strategy (in situ incubation) was used to assess the induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 by using the recommended probe substrate, i.e. phenacetin, bupropion, di...
Article
Full-text available
Pivampicillin (PIVA), an acyloxymethylester of ampicillin, is thought to enhance the oral bioavailability of ampicillin because of its greater lipophilicity compared to that of ampicillin. The fate of PIVA in intestinal cells and the exact location of its conversion into ampicillin have, however, never been unambiguously established. Polarized Caco...
Article
Full-text available
IL-10 is a cytokine mainly produced by macrophages that plays key roles in tolerance to inhaled antigens and in lung homeostasis. Its regulation in alveolar macrophages (HAM), the resident lung phagocytes, remains however unknown. The present study investigated the role of intracellular signalling and transcription factors controlling the productio...
Article
1.Despite increased awareness of aldehyde oxidase (AO) as a major drug-metabolizing enzyme, predicting the pharmacokinetics of its substrates remains challenging. Several drug candidates have been terminated due to high clearance, which were subsequently discovered to be AO substrates. Even retrospective extrapolation of human clearance, from model...
Chapter
This chapter focuses on factors influencing regional epithelial permeation of drugs related especially to transporters. It highlights the important key messages as regard to modified‐release formulations. Drug absorption for ionizable drugs is determined by the pH in the region of intended release. Uptake and efflux transporters expressed in the ga...
Article
The International Consortium for Innovation and Quality (IQ) Physiologically Based Pharmacokinetic modeling (PBPK) Induction Working Group (IWG) conducted a survey across participating companies around general strategies for PBPK modeling of induction, including experience with its utility to address various questions, regulatory interactions, and...
Article
Full-text available
PurposeMore accurate prediction of the extent of drug brain exposure in early drug discovery and understanding potential species differences could help to guide medicinal chemistry and avoid unnecessary animal studies. Hence, the aim of the current study was to validate the use of a P-gp transfected LLC-PK1 model to predict the unbound brain-to-pla...
Article
Early assessment of metabolism pathways of new chemical entities (NCEs) guides the understanding of drug-drug interactions (DDIs). Selective enzyme inhibitors are indispensable in cytochrome P450 (CYP) reaction phenotyping. The most commonly applied CYP2C19 inhibitor, omeprazole, lacks selectivity. Two promising alternatives, (+)-N-3-benzylnirvanol...
Article
Aims: To build and verify a PBPK model for radiprodil in adults and link this to a pharmacodynamic (PD) receptor occupancy (RO) model derived from in vitro data. Adapt this model to the paediatric population and predict starting and escalating doses in infants based on RO. Use the model to guide individualized dosing in a clinical trial in 2- to 1...
Article
Early determination of CYP3A4/5 contribution to the clearance of new chemical entities is critical to inform on the risk of drug-drug interactions with CYP3A inhibitors and inducers. Several in vitro approaches (recombinant P450 enzymes, correlation analysis, chemical and antibody inhibition in human liver microsomes) are available but they are usu...
Article
Full-text available
Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed and extensively biotransformed, and exh...
Article
Seletalisib is an orally bioavailable selective inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) in clinical development for the treatment of immune-mediated inflammatory diseases. The present study investigated the role of P-gp in seletalisib disposition, especially brain distribution, and the associated risks of interactions. Seletalisib was...
Article
Brivaracetam (BRV) is a new high affinity synaptic vesicle protein 2A ligand recently approved for adults with partial-onset seizures. As a support to in vitro metabolism assays, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method coupled to off-line solid phase extraction (SPE) was developed to quantify BRV acid metabolites, that is...
Article
Full-text available
Purpose: Vincristine is known to interfere with OATP-mediated uptake of other compounds, hinting that vincristine itself could be a substrate of OATP transporters. The present study therefore aimed to investigate the role of OATP transporters in the hepatocellular disposition of vincristine. Methods: Vincristine uptake was studied in suspended r...
Article
Phosphoinositide 3 kinases are targets for development of small-molecule inhibitors to disrupt progression of immune-inflammatory diseases. This phase 1 open-label study (Eudract 2014-005353-39) evaluated the safety and relative bioavailability of 2 new seletalisib (UCB5857) formulations (A and B) compared with a reference formulation. Absolute bio...
Article
Full-text available
The dissolution, intestinal absorption and presystemic metabolism of a drug depend on its physicochemical characteristics but also on numerous physiological (e.g. gastrointestinal pH, volume, transit time, morphology) and biochemical factors (e.g. luminal enzymes and flora, intestinal wall enzymes and transporters). Over the last decade, evidence h...
Article
Full-text available
Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present Phase I open-label two-way crossover study was designed to assess the effect of rifampin on the pharmacokinetics of BRV and its hydroxy (BRV-OH); acid (BRV-AC); and hydroxy acid (BRV OHAC) metaboli...
Article
1. Carbamazepine is an antiepileptic drug which is metabolized by CYP3A4 into carbamazepine-10,11-epoxide. This metabolite is then detoxified by epoxide hydrolase. As carbamazepine-10,11-epoxide has been associated with neurotoxicity, it is critical to identify whether a new antiepileptic drug has the potential to inhibit epoxide hydrolase and ther...
Chapter
Over the past 20 years, numerous examples of a concerted action between drug metabolising enzymes and transporters in the detoxification of drugs have been identified. Several mechanisms can be used to explain this interplay. First, uptake and efflux transporters can modulate the exposure of a drug to metabolising enzymes within the cell. There can...
Article
Full-text available
Objective: Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high-affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivara-cetam (BRV) for its rate of brain penetration and its onset of action. BRV was compared w...
Article
This phase I, open-label study investigated the effects of steady-state brivaracetam administration on steady-state pharmacokinetics of carbamazepine, and steady-state carbamazepine administration on single-dose and steady-state pharmacokinetics of brivaracetam, in 14 healthy participants who received brivaracetam 200mg single doses on days 1 and 2...
Article
Full-text available
CT7758, a carboxylate containing α4β1/α4/β7 integrin antagonist, was characterized for its pharmacokinetic profile in various in vitro and in vivo assays in support of clinical development. The oral bioavailability of CT7758 was 4 % in mice, 2 % in rats, 7-55 % in dogs, and 0.2 % in cynomolgus monkeys. The low bioavailability in rodents and monkey...
Article
OBJECTIVE: To characterize BRV for the risks of DDI and properties driving its permeability through the blood-brain barrier. BACKGROUND: BRV is a selective and high-affinity synaptic vesicle protein 2A ligand. BRV is orally bioavailable with rapid absorption, a t½ of 9h, linear pharmacokinetics, and a disposition minimally affected by hepatic or re...
Article
Full-text available
A new antiepileptic synaptic vesicle 2a (SV2a) ligand drug candidate was tested in 4-week oral toxicity studies in rat and dog. Brown pigment inclusions were found in the liver of high-dose dogs. The morphology of the deposits and the accompanying liver changes (increased plasma liver enzymes, increased total hepatic porphyrin level, decreased live...
Article
Purpose: Antiepileptic drugs (AEDs) do not effectively treat 30-40% of patients with epilepsy. Export of AEDs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier in drug-resistant patients, may be a mechanism for resistance to AEDs. For most recently approved AEDs, whether they are transported by Pgp is unkno...
Article
Full-text available
Brivaracetam (BRV) is a new high-affinity synaptic vesicle protein 2A ligand in phase III for epilepsy. Initial studies suggested that the hydroxylation of BRV into BRV-OH is supported by CYP2C8. Other metabolic routes include hydrolysis into a carboxylic acid derivative (BRV-AC), which could be further oxidized into a hydroxy acid derivative (BRV-...
Article
Full-text available
In the pharmaceutical industry, improving the early detection of drug-induced hepatotoxicity is essential as it is one of the most important reasons for attrition of candidate drugs during the later stages of drug development. The first objective of this study was to better characterize different cellular models (i.e., HepG2, HepaRG cells, and fres...
Conference Paper
CDP323 is an ethyl ester prodrug which is hydrolyzed into CT7758, the active carboxylic acid drug. CT7758 is a potent VLA4 antagonist and CDP323 was identified as a development candidate for the treatment of multiple sclerosis. In vitro metabolism data were generated using human intestinal (HIM) and liver microsomes (HLM) in order to characterize t...
Conference Paper
IL‑6 is well known to down-regulate in vitro the mRNA and protein levels of some P450 enzymes and the activities of hepatic transporters. In addition, there is also evidence of CYP450 suppression in patients with high level of IL-6 (inflammation, sepsis, heart failure, cancer, …). The purpose of the study was to evaluate directly the effect of IL-6...
Article
Introduction : Dans le poumon, une interaction physiologique s’établit continuellement entre les HAM (Human Alveolar Macrophages) et l’IgA, l’immunoglobuline la plus abondante des muqueuses présente à ce niveau surtout sous forme polymérique (pIgA). Des effets pro- et anti-inflammatoires de l’IgA sur les HAM ont été décrits, mais les mécanismes imp...
Article
Full-text available
The intracellular pharmacokinetics and pharmacodynamics of oritavancin (LY333328) were studied in cultured cells. Oritavancin was avidly accumulated by J774 and THP-1 macrophages and rat fibroblasts and to a lesser extent by LLC-PK1 and Caco-2 cells. In J774 macrophages, the level of accumulation reached a plateau (at 370-fold the extracellular con...
Article
Full-text available
To determine the intracellular accumulation in a macrophage cell line of ampicillin and ampicillin esters, and to measure their activity against intracellular Listeria monocytogenes. Quantitative evaluation of the activity of ampicillin, phthalimidomethylampicillin (PIMA) or pivaloyloxymethylampicillin (PIVA) against intracellular L. monocytogenes,...
Article
This article establishes the pharmacokinetic-pharmacodynamic parameters that are important when considering the intracellular activity of antibiotics. Generally speaking, the main classes of antibiotics seem to share globally the same properties against extracellular and intracellular organisms. The specific cellular pharmacokinetic properties may...
Article
Full-text available
The purpose of this work was to examine and understand the cellular pharmacokinetics of two basic esters of ampicillin, pivaloyloxymethyl (PIVA) and phthalimidomethyl (PIMA), in comparison with lysosomotropic drugs (chloroquine, azithromycin). Cell culture studies (J774 macrophages) were undertaken to study uptake and release kinetics and to assess...
Article
Full-text available
The influence of inhibitors of P-glycoprotein (verapamil [VE], cyclosporine [CY], and GF120918 [GF]) on the cell handling of macrolides (erythromycin [ERY], clarithromycin [CLR], roxithromycin [ROX], azithromycin [AZM], and telithromycin [TEL]) was examined in J774 murine macrophages. The net influx rates of AZM and TEL were increased from 2- to 3....
Article
Full-text available
Cefepime has been examined for stability, potential liberation of degradation products and compatibility with other drugs under conditions mimicking its potential use by continuous infusion in cystic fibrosis and intensive care patients (5-12% w/v solutions; temperatures from 20 to 37 degrees C; 1 h contact at 25 degrees C with other drugs frequent...
Article
Full-text available
The stability of antipseudomonal beta-lactams in concentrated solutions was examined in view of their potential administration by continuous infusion with external pumps (for intensive care patients) or with portable pumps carried under clothing (for cystic fibrosis patients). Aztreonam (100 g/liter), piperacillin (128 g/liter, with tazobactam), an...
Article
Full-text available
Saccharomyces boulardii is a non-pathogenic yeast which exerts trophic effects on human and rat small intestinal mucosa. To examine the effects of S boulardii on ileal adaptation after proximal enterectomy in rats. Wistar rats, aged eight weeks, underwent 60% proximal resection or transection and received by orogastric intubation either 1 mg/g body...
Conference Paper
Carbamazepine is one of the most commonly prescribed antiepileptic drugs. As it is frequently given in combination with other drugs, this could lead to drug‑drug interactions (DDI) with carbamazepine as drug victim or as drug perpetrator. One of the well‑known drug‑drug interactions with carbamazepine is related to the inhibition of epoxide hydrola...
Conference Paper
MRP2 belongs to the important family of ABC transporters. By its localization in the canalicular membrane of hepatocytes, it plays a significant role in the efflux of anionic compounds, glutathione and glucuronide conjugates into the bile. In addition, its expression at the intestinal and kidney level can also impact the absorption and urinary excr...

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