Processus de qualification d'un fournisseur de matières premières destinées à la production de principes actifs pharmaceutiques

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Harmonisation du système de formation (qualification au poste sur un site de production pharmaceutique vétérinaire)

L'industrie pharmaceutique est soumise à une réglementation particulièrement rigoureuse. En effet, elle doit garantir la qualité, l'efficacité et l'innocuité des médicaments qu'elle met sur le marché. Pour cela, cinq éléments essentiels doivent être parfaitement maîtrisés. Ce sont les 5M. C'est alors que la main d'œuvre figure parmi ces facteurs qui influent sur la qualité du médicament. La formation du personnel doit donc être parfaitement maîtrisée, non seulement par obligations réglementaires mais aussi pour le bon fonctionnement de l'entreprise. Apres avoir exposé les bases réglementaires qui régissent la formation du personnel, le système de qualification au poste est décrit par étapes : de l'accueil sur le site jusqu'aux critères de requalification. Enfin, la stratégie d'harmonisation du système de qualification au poste est expliquée : comment est né le projet et quelles actions ont été mises en place, et enfin pour illustrer cette démarche, un exemple d'harmonisation du système de qualification au poste est détaillé dans deux services du site de production vétérinaire.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Méthodologie générale de la validation des procédés de nettoyage dans l'industrie pharmaceutique (application à la validation de nettoyage d'une hydro-laveuse cessinox)

Le nettoyage des équipements et des locaux fait parti des opérations déterminantes dans le processus de production d'un produit pharmaceutique. Ces opérations contribuent à diminuer le risque de contamination en cours de fabrication entre lots d'un même produit ou entre lots de produits différents. La validation du nettoyage garantit que les procédés de fabrication sont mis en œuvre dans des locaux et avec du matériel propre. La validation de nettoyage doit être considérée comme l'un des moyens mis à la disposition du fabriquant pour lutter contre les risques de contamination en général, et contre le risque de contamination croisée entre produits. Ce moyen fait partie des actions d'assurance de la qualité communément mises en œuvre. Ce travail a pour objectif de présenter le nettoyage et sa validation sous leurs aspects théoriques puis pratiques. Nous aborderons dans un premier temps, les différents processus de contaminations et les moyens mis en œuvre pour les maîtriser. Nous proposerons dans une seconde partie une méthodologie générale de la validation de nettoyage : son principe, ses pré-requis et sa démarche qui sera dans une troisième partie, illustrée à travers un exemple concret de validation de nettoyage d'une hydro-laveuse CESSINOX.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Problématique de la gestion des contrefaçons par les laboratoires pharmaceutiques importateurs et exploitants en europe (moyens et procédures mises en œuvre)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Involvement of Pazopanib and Sunitinib Aldehyde Reactive Metabolites in Toxicity and Drug–Drug Interactions in Vitro and in Patient Samples

International audienceTyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug–drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug–drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time

The E glycoprotein plays an essential role in the high pathogenicity of European–Mediterranean IS98 strain of West Nile virus

International audienceno abstrac

Biological Role of Pazopanib and Sunitinib Aldehyde Derivatives in Drug-Induced Liver Injury

International audienceTyrosine kinase inhibitors pazopanib and sunitinib are both used to treat advanced renal cell carcinoma but expose patients to an increased risk of hepatotoxicity. We have previously identified two aldehyde derivatives for pazopanib and sunitinib (P-CHO and S-CHO, respectively) in liver microsomes. In this study, we aimed to decipher their role in hepatotoxicity by treating HepG2 and HepaRG hepatic cell lines with these derivatives and evaluating cell viability, mitochondrial dysfunction, and oxidative stress accumulation. Additionally, plasma concentrations of P-CHO were assessed in a cohort of patients treated with pazopanib. Results showed that S-CHO slightly decreased the viability of HepG2, but to a lesser extent than sunitinib, and affected the maximal respiratory capacity of the mitochondrial chain. P-CHO decreased viability and ATP production in HepG2. Traces of P-CHO were detected in the plasma of patients treated with pazopanib. Overall, these results showed that P-CHO and S-CHO affect hepatocyte integrity and could be involved in the pazopanib and sunitinib hepatotoxicity

Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor-positive breast cancer: Results of the OXYTAM study

International audienceAccumulating evidence indicates that cholesterol oxygenation products, also known as oxysterols (OS), are involved in breast cancer (BC) promotion. The impact of Tam, as well as aromatase inhibitors (AI), an alternative BC endocrine therapy (ET), on OS metabolism in patients is currently unknown. We conducted a prospective clinical study in BC patients receiving Tam (n=15) or AI (n=14) in adjuvant or in metastatic settings. The primary end point was the feasibility of detecting and quantifying 11 different OS in the circulation of patients before and after 28days of treatment with Tam or AI. Key secondary end points were the measurements of variations in the concentrations of OS according to differences between patients and treatments. OS profiling in the serum of patients was determined by gas chromatography coupled to mass spectrometry. OS profiling was conducted in all patients both at baseline and during treatment regimens. An important inter-individual variability was observed for each OS. Interestingly 5,6β-epoxycholesterol relative concentrations significantly increased in the entire population (p=0.0109), while no increase in Cholestane-triol (CT) levels was measured. Interestingly, we found that, in contrast to AI, Tam therapy significantly decreased blood levels of 24-hydroxycholesterol (24-HC), 7α-HC and 25-HC (a tumor promoter) (p=0.0007, p=0.0231 and p=0.0231, respectively), whereas 4β-HC levels increased (p=0.0010). Interestingly, levels of 27-HC (a tumor promoter) significantly increased in response to AI (p=0.0342), but not Tam treatment. According to these results, specific OS are promising candidate markers of Tam and AI efficacy. Thus, further clinical investigations are needed to confirm the use of oxysterols as biomarkers of both prognosis and/or the efficacy of ET

Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase

International audiencePyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. Furthermore, we illustrate the human-specific nature of this mechanism, as mouse macrophages do not express substantial levels of thymidine phosphorylase, which constrains the applicability of mouse models. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. Additionally, our findings revealed that macrophages represent a significant source of thymidine phosphorylase expression, comprising over 40 % of the expressing cells, in human colorectal cancer, thereby contributing to chemoresistance