Approches pharmacocinétiques/pharmacodynamiques appliquées au développement d'un nouvel inhibiteur direct du facteur Xa pour le traitement de la thrombose artérielle

L'otamixaban est un nouvel inhibiteur direct du FXa, en développement pour le traitement intraveineux de la thrombose artérielle. L'objectif de ce travail de pharmacologie clinique vise l'étude des propriétés pharmacocinétiques (PK) et pharmacodynamiques (PD) de l'otamixaban ainsi que l'élaboration de modélisations et simulations (M&S) en support des études de Phase II/III à partir des données chez le sujet sain et chez le patient coronarien chronique. Une "empreinte PK/PD des marqueurs de l'effet anticoagulant" a été genérée, incluant les mesures d'activité anti-FXa, des temps de coagulation (aPTT, PT, dPT, RVVT et HCT), et de l'inhibition de la génération de thrombine. La non-proportionalité de la pharmacocinétique de l'otamixaban à la dose a été explorée et intégrée dans les modèles pharmacocinétiques. L'absence d'effet majeur sexe et age sur les paramètres PK et PD a été démontrée. Enfin, l'absence d'interaction médicamenteuse et la complémentarité des effets anticoagulants de l'otamixaban et des effets anti-plaquettaires des modificateurs de la fonction plaquettaires a été demontrée pour le tirofiban et pour l'acide acétyle salicylique..Otamixaban, is a novel direct FXa inhibitor for the treatment of arterial thrombosis. This clinical pharmacology work aims the study of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of otamixaban as well as the development of modeling and simulations (M&S) to support the Phase II/III studies using data in healthy subjects and in chronic coronary patients. A fingerprint of PK/PD markers for anticoagulant effect was generated, including the measurements of anti-FXa activity, of clotting times (aPTT, PT, dPT, RVVT et HCT) and of the inhibition of thrombin generation. The non-dose proportional pharmacokinetics of otamixaban was investigated and built into the pharmacokinetic models. The lack of a major gender and age effect on the PK and PD parameters was demonstrated. Finally, the absence of any drug-drug interactions and the complementarities of the anticoagulant effect of OTAM and of the anti-platelet effects of modifiers of the platelet function has been reported for tirofiban and acetyl salicylic acid.PARIS-BIUP (751062107) / SudocSudocFranceF

Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma

RATIONALE: The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma. Objective: We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies. METHODS: The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9. RESULTS: AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883. CONCLUSIONS: Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonist

First-In-Human Study of Cemiplimab Alone or In Combination with Radiotherapy and/or Low Dose Cyclophosphamide in Patients with Advanced Malignancies.

PURPOSE: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLTs), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m RESULTS: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculo-papular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; seven had a partial response. Observed duration of response was ≥12 months in six patients. CONCLUSIONS: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs. Cemiplimab exhibited encouraging antitumor activity and durable responses