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Graphical AbstractSAPT: single antiplatelet therapy; DAPT: dual antiplatelet therapy; TAVR: transcatheter aortic valve replacement; CI: confidence interval

Background and Objectives: In vitro evaluation of the P-glycoprotein (P-gp) inhibitory potential is an important issue when predicting clinically relevant drug–drug interactions (DDIs). Located within all physiological barriers, including intestine, liver, and kidneys, P-gp plays a major role in the pharmacokinetics of various therapeutic classes. However, few data are available about DDIs involving renal transporters during the active tubular secretion of drugs. In this context, the present study was designed to investigate the application of the human renal cell line RPTEC/TERT1 to study drug interactions mediated by P-gp. Methods: The P-gp inhibitory potentials of a panel of drugs were first determined by measuring the intracellular accumulation of rhodamine 123 in RPTEC/TERT1 cells. Then four drugs were selected to assess the half-maximal inhibitor concentration (IC50) values by measuring the intracellular accumulation of two P-gp-substrate drugs, apixaban and rivaroxaban. Finally, according to the FDA guidelines, the [I1]/IC50 ratio was calculated for each combination of drugs to assess the clinical relevance of the DDIs. Results: The data showed that drugs which are known P-gp inhibitors, including cyclosporin A, ketoconazole, and verapamil, caused great increases in rhodamine 123 retention, whereas noninhibitors did not affect the intracellular accumulation of the P-gp substrate. The determined IC50 values were in accordance with the inhibition profiles observed in the rhodamine 123 accumulation assays, confirming the reliability of the RPTEC/TERT1 model. Conclusions: Taken together, the data demonstrate the feasibility of the application of the RPTEC/TERT1 model for evaluating the P-gp inhibitory potentials of drugs and consequently predicting renal drug interactions.

Meta‐analyses are widely used to strengthen available evidence and obtain more precise estimates of treatment effect than any individual trial. Paradoxically, multiplication of meta‐analyses on the same topic can lead to confusion as practitioners no longer benefit from a rapid and synthetic response. This phenomenon may appear disproportionate when the number of published meta‐analyses exceeds the number of original studies. To describe an example of redundant meta‐analyses published in the same area with the same randomized clinical trials (RCTs). A systematic review was performed to identify all published meta‐analyses of original RCTs that compared direct oral anticoagulants with low molecular weight heparins in cancer patients with venous thromboembolism (VTE). Forest plots were used to represent the meta‐analyses results for efficacy (VTE recurrence) and safety (major bleeding) endpoints. An authors’ network was constructed to explore the links between the authors of the published meta‐analyses. In the past 3 years, four original RCTs were the subject of 20 published meta‐analyses by 142 authors: five, four, and 11 meta‐analyses pooled the data of two, three, and four RCTs, respectively. The results of meta‐analyses were similar regarding the risks of VTE recurrence and major bleeding. The 11 meta‐analyses of four RCTs were published within 6 months of the publication of the last RCT. The epidemic proportions of such redundant literature and authorship could be moderated by developing “living” meta‐analyses and encouraging authors of new RCTs to update the corresponding meta‐analysis in the same paper as their original research.

Detection of severe renal impairment in patients with venous thromboembolism (VTE) is mandatory both for selecting anticoagulant therapy and for evaluating major bleeding risk, increased by severe renal impairment.

Le conflit fémoro-acétabulaire (CFA) associé à une dysplasie acétabulaire contre indique le traitement du conflit sous arthroscopie notamment en cas de pince, mais cette donnée est débattue notamment en cas de dysplasie modérée et en cas d’effet came isolé. Aussi nous avons mené une étude cas témoin comparant un groupe de patients présentant une dysplasie limite (VCE de 20 à 24°C), modérée (VCE de 15 à 19°) et sévère (VCE<15°) (Groupe D) versus un groupe témoin apparié ayant une couverture acétabulaire normale (VCE 25–30°). Les objectifs étaient : 1) de préciser les résultats fonctionnels et la satisfaction, 2) de corréler les résultats fonctionnels à l’importance de la dysplasie et à l’importance de la came.

Nonlinear mixed effect models are classical tools to analyze nonlinear longitudinal data in many fields such as population pharmacokinetics. Groups of observations are usually compared by introducing the group affiliations as binary covariates with a reference group that is stated among the groups. This approach is relatively limited as it allows only the comparison of the reference group to the others. The proposed method compares groups using a penalized likelihood approach. Groups are described by the same structural model but with parameters that are group specific. The likelihood is penalized with a fused lasso penalty that induces sparsity in the differences between groups for both fixed effects and variances of random effects. A penalized Stochastic Approximation EM algorithm is proposed that is coupled to Alternating Direction Method Multipliers to solve the maximization step. An extensive simulation study illustrates the performance of this algorithm when comparing more than two groups. Then the approach is applied to real data from two pharmacokinetic drug–drug interaction trials. [ABSTRACT FROM AUTHOR]

Les anticoagulants oraux directs offrent une alternative aux médicaments antivitamines K dans la prévention et le traitement des événements thromboemboliques. Contrairement à ces derniers, ils inhibent de façon directe et spécifique certains facteurs de la coagulation (Xa, IIa). Leurs propriétés pharmacologiques permettent une administration à dose fixe et sans suivi biologique pour la majorité des patients. Néanmoins, leur pharmacocinétique dépendante de transporteurs membranaires (glycoprotéine P [P-gp]) et des cytochromes P450 (CYP3A4) les exposent à des interactions médicamenteuses non négligeables. Une adaptation posologique peut alors s’avérer nécessaire tout comme dans certaines situations cliniques, comme l’insuffisance rénale ou hépatique. Cependant certaines questions restent ouvertes, en particulier sur le maniement optimal de ces médicaments dans certaines populations, qui cumulent plusieurs sources de variabilité.

Nonlinear Mixed effects models are hidden variables models that are widely used in many fields such as pharmacometrics. In such models, the distribution characteristics of hidden variables can be specified by including several parameters such as covariates or correlations which must be selected. Recent development of pharmacogenomics has brought averaged/high dimensional problems to the field of nonlinear mixed effects modeling for which standard covariates selection techniques like stepwise methods are not well suited. The selection of covariates and correlation parameters using a penalized likelihood approach is proposed. The penalized likelihood problem is solved using a stochastic proximal gradient algorithm to avoid inner-outer iterations. Speed of convergence of the proximal gradient algorithm is improved using component-wise adaptive gradient step sizes. The practical implementation and tuning of the proximal gradient algorithm are explored using simulations. Calibration of regularization parameters is performed by minimizing the Bayesian Information Criterion using particle swarm optimization, a zero-order optimization procedure. The use of warm restart and parallelization allowed computing time to be reduced significantly. The performance of the proposed method compared to the traditional grid search strategy is explored using simulated data. Finally, an application to real data from two pharmacokinetics studies is provided, one studying an antifibrinolytic and the other studying an antibiotic. [ABSTRACT FROM AUTHOR]

Inflammation is characterized by an increased secretion of proinflammatory cytokines known to alter the expression and functionality of drug transporters. Since P-glycoprotein (P-gp) plays a key role in the pharmacokinetics of several drugs, these modulations could further affect drug exposure. In this context, this study aims to investigate the impact of in vitro cytokine exposure on the expression and activity of P-gp using the intestinal model Caco-2 and the human renal cells RPTEC/TERT1. Cells were exposed to various concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β for 24 or 72 h. Gene expression was then assessed by RT-qPCR followed by absolute quantification of P-gp using liquid chromatography coupled with mass spectrometry. Then, the activity of P-gp was assessed by the intracellular accumulation of rhodamine 123. TNF-α increased both the gene expression and P-gp activity by 15–40% in each model. Minor modulations were observed at the protein level with increases of up to 8% for RPTEC/TERT1 cells and 24% for Caco-2 cells. Conversely, IL-1β led to a downregulation of gene, protein, and functionality by 48 and 25% in intestinal and renal cells, respectively. Taken together, these data highlighted that gene expression levels and functional activity of P-gp are altered by the pro-inflammatory cytokines in intestinal and renal cells. Such pronounced changes in human P-gp could result in altered exposure to drug substrates. Further in vivo studies are needed to confirm the impact of inflammation on drug pharmacokinetics.

La chirurgie arthroscopique a démontré son intérêt dans le traitement des conflits fémoro-acétabulaires (CFA) symptomatiques. Cependant, le seuil d’état arthrosique garantissant des résultats postopératoires favorables reste imprécis.