Drug–drug interaction prediction of ziritaxestat using a physiologically based enzyme and transporter pharmacokinetic network interaction model

Abstract Ziritaxestat, an autotaxin inhibitor, was under development for the treatment of idiopathic pulmonary fibrosis. It is a substrate of cytochrome P450 3A4 (CYP3A4) and P‐glycoprotein and a weak inhibitor of the CYP3A4 and OATP1B1 pathways. We developed a physiologically based pharmacokinetic (PBPK) network interaction model for ziritaxestat that incorporated its metabolic and transporter pathways, enabling prediction of its potential as a victim or perpetrator of drug–drug interactions (DDIs). Concurrently, we evaluated CYP3A4 autoinhibition, including time‐dependent inhibition. In vitro information and clinical data from healthy volunteer studies were used for model building and validation. DDIs with rifampin, itraconazole, voriconazole, pravastatin, and rosuvastatin were predicted, followed by validation against a test dataset. DDIs of ziritaxestat as a victim or perpetrator were simulated using the final model. Predicted‐to‐observed DDI ratios for the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) were within a two‐fold ratio for both the metabolic and transporter‐mediated simulated DDIs. The predicted impact of autoinhibition/autoinduction or time‐dependent inhibition of CYP3A4 was a 12% decrease in exposure. Model‐based predictions for ziritaxestat as a victim of DDIs with a moderate CYP3A4 inhibitor (fluconazole) suggested a 2.6‐fold increase in the AUC of ziritaxestat, while multiple doses of a strong inhibitor (voriconazole) would increase the AUC by 15‐fold. Efavirenz would yield a three‐fold decrease in the AUC of ziritaxestat. As a perpetrator, ziritaxestat was predicted to increase the AUC of the CYP3A4 index substrate midazolam by 2.7‐fold. An overarching PBPK model was developed that could predict DDI liability of ziritaxestat for both CYP3A4 and the transporter pathways

A new impedimetric biosensor for the assessment of endocrine-disrupting compounds binding affinity for estrogen receptor-α. Principle and first results

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Electrochemical estrogen receptor a based biosensor for label-free detection of estradiol

International audienceWe describe a new electrochemical biosensor based on estrogen receptor (ER-) for label-free detection of 17-estradiol, a model of endocrine-disrupting compounds. ER- is coupled onto the gold electrode through its 6-His tag and NTA-copper complex. After interaction of estradiol with ER-, the biosensor presents a well-defined peak at +500mV due to estradiol oxidation (E17 peak). The linear range of detection is from 1fM to 1nM and the detection limit is 1fM. Good selectivity was obtained for interfering substances at nanomolar level, for concentration of E17 up to 0.1pM. The E17 was detected in hospital effluents

Biocapteur bimézymétrique conductimétrique pour la détection d'ions des métaux lourds et des pesticides dans des les eaux, basés sur l'inhibition enzymatique d'Arthrospira platensis

International audienceAn original bi-enzymatic biosensor was designed by immobilizing Arthrospira platensis cells, called Spirulina, on gold interdigitated transducers. Phosphatase and esterase activities were inhibited, respectively, by heavy metals and by pesticides. Inhibition activities were observed with different mixtures of pesticides + heavy metals. The quantification limits for Cd2+ and Hg2+ are 10−20 M in mixture and in pure solution. The quantification limits of parathion-methyl, paraoxon-methyl and triazine are respectively 10−20 M, 10−18 M and 10−20 M in mixture and pure solutions. These results show that there is no synergistic effect between the two families of pollutants. Qualitative contamination of effluent samples and their purification after passing through a municipal wastewater treatment plant were observed by our bi-enzymatic biosensor and confirmed by classical analytical techniques for heavy metal ions

Development of new graphene-substrate materials through laser technology for electrochemical sensing applications

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GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy

Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne muscular dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30mg/kg, 6 day/week s.c.), and the results were compared with those from the administration of α-methylprednisolone (PDN; 1mg/kg, i.p.) and nandrolone (NAND, 5mg/kg, s.c.). This assessment was followed by a 12-week dose-dependence study (0.3-30mg/kg s.c.). The outcomes were evaluated in vivo and ex vivo on functional, histological and biochemical parameters. Similar to PDN and NAND, GLPG0492 significantly increased mouse strength. In acute exhaustion tests, a surrogate of the 6-min walking test used in DMD patients, GLPG0492 preserved running performance, whereas vehicle- or comparator-treated animals showed a significant increase in fatigue (30-50%). Ex vivo, all drugs resulted in a modest but significant increase of diaphragm force. In parallel, a decrease in the non-muscle area and markers of fibrosis was observed in GLPG0492- and NAND-treated mice. The drugs exerted minor effects on limb muscles; however, electrophysiological biomarkers were ameliorated in extensor digitorum longus muscle. The longer dose-dependence study confirmed the effect on mdx mouse strength and resistance to fatigue and demonstrated the efficacy of lower drug doses on in vivo and ex vivo functional parameters. These results support the interest of further studies of GLPG0492 as a potential treatment for DMD.Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne muscular dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30 mg/kg, 6 day/week s.c.), and the results were compared with those from the administration of α-methylprednisolone (PDN; 1 mg/kg, i.p.) and nandrolone (NAND, 5 mg/kg, s.c.). This assessment was followed by a 12-week dose-dependence study (0.3-30 mg/kg s.c.). The outcomes were evaluated in vivo and ex vivo on functional, histological and biochemical parameters. Similar to PDN and NAND, GLPG0492 significantly increased mouse strength. In acute exhaustion tests, a surrogate of the 6-min walking test used in DMD patients, GLPG0492 preserved running performance, whereas vehicle- or comparator-treated animals showed a significant increase in fatigue (30-50%). Ex vivo, all drugs resulted in a modest but significant increase of diaphragm force. In parallel, a decrease in the non-muscle area and markers of fibrosis was observed in GLPG0492- and NAND-treated mice. The drugs exerted minor effects on limb muscles; however, electrophysiological biomarkers were ameliorated in extensor digitorum longus muscle. The longer dose-dependence study confirmed the effect on mdx mouse strength and resistance to fatigue and demonstrated the efficacy of lower drug doses on in vivo and ex vivo functional parameters. These results support the interest of further studies of GLPG0492 as a potential treatment for DMD. © 2013 Elsevier Ltd. All rights reserved