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Basiliximab, an anti-CD25 chimeric monoclonal antibody, is approved in prevention of acute kidney transplant rejection. This study aims at investigating target-mediated pharmacokinetics of basiliximab.Data from the IDEALE study, where 16 kidney transplant patients were treated with 2 40- or 80-mg basiliximab injections, were reanalysed. Basiliximab pharmacokinetics was described using a population 2-compartment target-mediated drug disposition model with the quasi-steady-state approximation.Volume of distribution was significantly higher in males (P = .029). Estimated baseline target antigen (CD25) level was lower is patients cotreated with cyclosporine (P = .026).This analysis allows the first description of the target-mediated nonlinear elimination of basiliximab. Our results suggest that cyclosporine cotreatment is associated with decreased target level and that an optimized dosing regimen may improve basiliximab effects.

BackgroundStandard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first step therapies while rituximab is used as rescue therapy.MethodsIn a randomised, double blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune feature) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinico-biological data and a NSIP-like HRCT pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for six months. The primary endpoint was the change in percent of predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary endpoints included progression-free survival (PFS) up to 6 months and safety.FindingsBetween January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se1.13) in the rituximab+MMF group and −2.01 (se1.17) in the placebo+MMF group (between-group difference, 3.60 [95% CI 0.41 to 6.80]; p=0.0273). PFS was better in the rituximab+MMF group (crude HR 0.47 [95%CI 0.23 to 0.96]; p=0.03). Serious adverse events occurred in 26 patients of the rituximab+MMF group (41%) and in 23 of the placebo+MMF group (39%). Nine infections were reported in the rituximab+MMF group (five bacterial infections, 3 viral infections, 1 other) and four bacterial infections in the placebo+MMF group.InterpretationCombination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must consider the risk of viral infection.

International audience; Abstract The cellular prion protein PrP C partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrP C and CAV1 across cancer. Using cell-based assays, we show that PrP C regulates the expression of and interacts with CAV1. PrP C additionally controls the expression of the amyloid precursor protein APP and of the Aβ generating enzyme BACE1, and regulates the levels of Aβ, whose accumulation is a central event in Alzheimer’s disease. We further identify DKK1 and DKK3, involved in both Alzheimer’s disease and cancer progression, as targets of the PrP C -dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrP C interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aβ-PrP C -dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aβ-PrP C axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer.

Monoclonal antibodies are therapeutic monoclonal Ig that act by highly specific binding to their target antigen and by interacting with the immune system. Their side effects are mainly related to their mechanism of action. The most frequent adverse effects are infusion reactions. Post-marketing surveillance is essential for identifying adverse reactions and improving knowledge of their mechanism of action.

Infliximab, an anti-tumour necrosis factor (TNF)-α monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn’s disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn’s disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn’s disease, assuming ankylosing spondylitis with no target-mediated elimination. The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration–time data. Estimated baseline TNF-α amounts were similar in Crohn’s disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn’s disease than in rheumatoid arthritis (kint = 0.024 vs 0.061 day−1, respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn’s disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-α inhibition may not be sustained over the entire dose interval. The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-α, especially in patients with Crohn’s disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-α inhibition.

Importance Systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) is a matter of debate and regular updates are necessary. Objective To evaluate systemic adverse events (SAEs) associated with intravitreal anti-VEGF drugs compared with non-anti-VEGF treatments in patients with ocular diseases. Data sources Electronic searches were conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception to July 7, 2020. Study selection Randomized clinical trials conducted in adults with retinal diseases who received intravitreal anti-VEGF drugs. Data extraction and synthesis Studies and treatment characteristics and outcome data were extracted and analyzed, and study quality was evaluated. Main outcomes and measures Main outcomes were major cardiovascular events (MACEs) and total mortality. Secondary outcomes included nonocular hemorrhage, components of MACEs, other cardiovascular outcomes, serious SAEs, and all SAEs. Results A total of 74 randomized clinical trials were analyzed: 32 trials (43%) included 14 190 patients with age-related macular degeneration (AMD), 24 (32%) included 5424 patients with diabetic retinopathy (diabetic macular edema or proliferative diabetic retinopathy), 17 trials (23%) included 3757 patients with retinal vein occlusion, and 1 trial (1%) included 122 patients with myopic choroidal neovascularization. Anti-VEGF drug administration did not increase MACEs compared with control agents (odds ratio [OR], 1.16; 95% CI, 0.85-1.58) or total mortality (OR, 1.27; 95% CI, 0.82-1.96). There was an interaction (subgroup difference, P = .04) in mortality risk depending on the underlying disease with an increase (OR, 1.80; 95% CI, 1.03-3.16; P = .04) in the risk of death in patients with diabetic retinopathy; however, no increase was observed in patients with AMD or retinal vein occlusion. Administration of anti-VEGF drugs increased the risk of nonocular hemorrhage (OR, 1.46; 95% CI, 1.01-2.10), mainly in patients with AMD. Conclusions and relevance Intravitreal anti-VEGF was not associated with an increase in MACEs in the trials examined herein. Increased mortality in patients with diabetes and nonocular hemorrhages, especially in those with AMD, could represent a safety signal, but the evidence was not strong. However, continued surveillance of SAEs remains warranted.

Introduction Nonspecific interstitial pneumonia (NSIP) are rare but severe diseases, with high mortality and morbidity, with no effective pharmacological treatment allowing for long-term remission, and therefore no clear therapeutic recommendations. Classic immunosuppressants are used as first-line treatment, with only one third of patients being responders and no clear recommendations exist for the choice of the second-line therapy. The EvER-ILD study is the first one to prospectively evaluate the efficacy and safety of rituximab and mycophenolate mofetil (MMF) versus placebo and MMF in a broad range of NSIP patients that did not respond to a first-line therapy. A pharmacokinetic-pharmacodynamic analysis based on rituximab serum concentrations will allow identification of potential factors associated with therapeutic response and/or adverse effects. Methods EvER-ILD study is a French multicenter, prospective, randomized, double blind, placebo-controlled, superiority trial. Patients with severe and progressive NSIP non-responding to a first line immunosuppressive treatment will be randomized in 2 groups of treatment: one course of rituximab plus 6 months MMF (RTX-MMF group) and one course of placebo plus 6 months MMF (Placebo-MMF group). The primary outcome is the change in Forced Vital Capacity (FVC, % of predicted) from baseline to 6 months. Several clinical, biological, and quality of life secondary outcomes will be measured at 3, 6 and 12 months. A sample size of 122 patients (61 patients per group) would allow to show a point difference between groups in the change of FVC at 6 months, based on a common standard deviation for FVC change of 8% with a power of 90%, alpha 5% two-sided, and anticipating an extreme 10% drop-out rate. Ethics and dissemination The protocol was approved by the French Research Ethics Committee (CPP Tours Ouest 1 2016-R28) on November 10, 2016, and by the French competent authority (ANSM, reference 160771A-22) on December 1st, 2016. This article refers to protocol V2, dated November 18, 2016. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. Results will be disseminated via peer reviewed publication and presentation at international conferences. Trial registration number NCT02990286 (clinicaltrials.gov), EudraCT 2016-003026-16 (European Medicines agency).

Background PCSK9 antibodies are novel potent and expansive lipid lowering agents that demonstrated clinical benefit in high risk patients. We hypothesized that optimization of dose and administration schedule, ideally adapted to the target population, could reduce costs while maintaining the clinical benefit. Objective To explore the relationship between LDL-Cholesterol (LDL-C) decrease by anti-PCSK9 monoclonal antibodies and several covariates such as drug dose, administration schedule, baseline LDL-C, population and statins. Methods We performed systematic review, meta-analysis and meta-regression of randomized controlled trials that compared alirocumab or evolocumab to placebo or no treatment and reported LDL-C decrease, with a minimum follow-up of 12 weeks and with a sample size of 30 patients or more. Electronic searches of MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov from inception to March 2019. We evaluated the quality of included studies and extracted aggregate data. We used random effect models and multivariate multilevel meta-regression to explore factors influencing LDL-C decrease. All analyses were performed with R. Results From 1479 references identified and screened on title/abstract, the full texts of 72 articles were screened. We included 32 studies (31 references.) Anti-PCSK9 mAbs decreased LDL-C by 53%, 95% CI (−56% to −50%), with no significant difference between the two drugs (p=0.07). In univariate meta-regressions, higher baseline LDL-C level, monthly administration, higher percentage of patients with high-dose statins were associated with a lower LDL-C decrease (p (p Conclusion Alirocumab and evolocumab showed substantial LDL-C reductions in clinical trials, without significant differences in their biological efficacies. A higher baseline LDL-C, higher intensity of statin co-treatment and a lower dose seemed to negatively influence LDL-C decrease. Funding Acknowledgement Type of funding source: None

PRESCRIPTION OF FIXED DOSE COMBINATIONS OF ANTIHYPERTENSIVE DRUGS. Many fixed-dose antihypertensive combinations are available for treating hypertension. Compared to free associations, fixed-dose combinations have major advantages including a well-defined dose-ratio and a better adherence. The later leads to higher antihypertensive efficacy and faster blood pressure lowering effect, particularly interesting in patients at high cardiovascular risk, and to a lower cost of global medical care. However, fixed-dose combinations have some theorical limitations that need to be evaluated in clinical practice: a reduced detection of the possible inefficacy of one of the medications, a reduced possibility of combining different dosages, an increased risk of misuse, and a higher risk of complications in case of non-adherence. Fixed-dose combination therapies are insufficiently prescribed for first-line antihypertensive treatment despite an increasing level of evidence and their recommendations by learned societies. Triple fixed-dose combinations, prescribed as second-line antihypertensive treatment, are not yet reimbursed by health care systems. Drug companies should be encouraged to perform large randomized controlled clinical trials, in order to demonstrate that fixeddose combination therapies, prescribed first-line, increase short and long-term adherence compared to free associations, and thus lower blood pressure to a higher extent, ultimately leading to a lower incidence of cardiovascular complications.PRESCRIPTION DES ASSOCIATIONS FIXES D’ANTIHYPERTENSEURS. Pour le traitement de l’hypertension artérielle, le médecin dispose d’un grand nombre d’associations thérapeutiques fixes. Celles-ci présentent des atouts importants par rapport aux associations libres : un rapport de posologie rigoureusement étudié et une meilleure observance. La meilleure observance est source d’efficacité antihypertensive supplémentaire et d’une plus grande rapidité d’action particulièrement intéressante chez les patients à haut risque cardiovasculaire, à un moindre coût de la prise en charge médicale globale. Les limites des associations fixes par rapport aux associations libres sont théoriques et nécessitent d’être évaluées en pratique : moindre détection d’une possible inefficacité d’un des deux médicaments, restriction des possibilités de combinaison de posologies, plus fréquent mésusage, et dangerosité en cas d’inobservance. En première intention, les bithérapies fixes restent insuffisamment prescrites malgré un niveau de preuve croissant alors que leur utilisation est maintenant recommandée par les sociétés savantes européennes. Les combinaisons fixes triples d’antihypertenseurs, prescrites en deuxième intention, ne font pas encore l’objet d’un remboursement. Les industriels du médicament devraient être encouragés à mettre en place des essais thérapeutiques randomisés qui prendraient en compte l’amélioration de l’observance à court et à long terme, la baisse de la pression artérielle et la réduction des complications cardiovasculaires.

Infarct size is a major prognostic factor in ST-segment elevation myocardial infarction (STEMI). It is often assessed using repeated blood sampling and the estimation of biomarker area under the concentration versus time curve (AUC) in translational research. We aimed at developing limited sampling strategies (LSS) to accurately estimate biomarker AUC using only a limited number of blood samples in STEMI patients. This retrospective study was carried out on pooled data from five clinical trials of STEMI patients (TIMI blood flow 0/1) studies where repeated blood samples were collected within 72 h after admission to assess creatine kinase (CK), cardiac troponin I (cTnI) and muscle-brain CK (CK-MB). Biomarker kinetics was assessed using previously described biomarker kinetic models. A number of LSS models including combinations of 1 to 3 samples were developed to identify sampling times leading to the best estimation of AUC. Patients were randomly assigned to either learning (2/3) or validation (1/3) subsets. Descriptive and predictive performances of LSS models were compared using learning and validation subsets, respectively. An external validation cohort was used to validate the model and its applicability to different cTnI assays, including high-sensitive (hs) cTnI. 132 patients had full CK and cTnI dataset, 49 patients had CK-MB. For each biomarker, 180 LSS models were tested. Best LSS models were obtained for the following sampling times: T4–16 for CK, T8–T20 for cTnI and T8–T16 for CK-MB for 2-sample LSS; and T4–T16–T24 for CK, T4–T12–T20 for cTnI and T8–T16–T20 for CK-MB for 3-sample LSS. External validation was achieved on 103 anterior STEMI patients (TIMI flow 0/1), and the cTnI model applicability to recommended hs cTnI confirmed. Biomarker kinetics can be assessed with a limited number of samples using kinetic modelling. This opens the way for substantial simplification of future cardioprotection studies, more acceptable for the patients.

Monoclonal antibodies are therapeutic monoclonal Ig that act by highly specific binding to their target antigen and by interacting with the immune system. Their side effects are mainly related to their mechanism of action. The most frequent adverse effects are infusion reactions. Post-marketing surveillance is essential for identifying adverse reactions and improving knowledge of their mechanism of action.

Background Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature. Methods The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis. Results Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p Conclusion This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.

RESUME Il existe un paradoxe entre d’un cote le grand nombre de molecules disponibles et bon marche et la quasi-gratuite des medicaments et d’autre part leur sous-utilisation par inertie therapeutique et inobservance. Nous souhaitons souligner ici certaines imperfections concernant les traitements antihypertenseurs en France et suggerer quelques moyens de les corriger. Cela concerne en premier lieu l’utilisation des generiques. Nous proposons la generalisation de la prescription DCI (Denomination Commune Internationale) et l’utilisation par le patient d’un generique de la meme marque tout au long de son traitement pour eviter toute erreur de prise et favoriser l’observance medicamenteuse. Le deuxieme probleme concerne les bitherapies fixes d’antihypertenseurs de premiere intention, insuffisamment prescrites malgre un niveau de preuve croissant alors que leur utilisation est maintenant recommandee par les societes savantes europeennes. Il est necessaire de sensibiliser les medecins et les patients, ainsi que les industriels du medicament a l’interet de controler rapidement l’hypertension. La troisieme imperfection concerne l’absence de remboursement des combinaisons fixes triples d’antihypertenseurs, prescrites en deuxieme intention. Les industriels du medicament devraient etre encourages a mettre en place des essais therapeutiques randomises qui prendraient en compte l’amelioration de l’observance a court et a long terme, la baisse de la pression arterielle et la reduction des complications cardiovasculaires, de maniere a convaincre les membres de la Commission de la Transparence de la Haute Autorite de Sante (HAS) et obtenir ainsi un remboursement. Enfin, de maniere plus specifique, la prescription d’eplerenone devrait etre autorisee et remboursee en cas d’HTA resistante sans hyperaldosteronisme primaire chez les patients intolerants a la spironolactone.

Summary Background The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized. Aim To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting. Methods We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data. Results MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58–7.07), peripheral oedema (OR 2.87 95% CI 1.93–4.27) and syncope (OR 6.71, 95% CI 3.00–14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03–10.09), peripheral oedema (arOR 1.39, 95% CI 1.17–1.66), syncope (arOR 1.56, 95% CI 1.22–1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04–7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21–1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach. Conclusions In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.

International audience; Before menopause, women are protected from the risk of hypertension and atherosclerosis by endogenous estrogens. Estrogens have a vasoprotective role, while progesterone seems to have a neutral effect. Exogenous estrogens used in menopausal treatment have vascular effects. These effects depend of type, dose and administration type, and with age and atherosclerosis stages. Synthetic progestins have varying clinical effects. Each drug must be evaluated separately.

Background Mineralocorticoid receptor antagonists ( MRA s) have emerged as potential atrial fibrillation ( AF ) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRA s on AF occurrence and explore factors that could influence the magnitude of the effect size. Methods and Results PubMed, Embase, and Cochrane Central databases were used to search for randomized clinical trials and observational studies addressing the effect of MRA s on AF occurrence from database inception through April 03, 2018. We performed a systematic review and random effects meta‐analyses to compute odds ratios with 95% CI s. Meta‐regression was then applied to explore the sources of between‐study heterogeneity. We included 24 studies, 11 randomized clinical trials and 13 observational cohorts, representing a total number of 7914 patients (median age: 64.2 years; median left ventricular ejection fraction: 49.7%; median follow‐up: 12.0 months), 2843 (35.9%) of whom received MRA therapy. Meta‐analyses showed a significant overall reduction in AF occurrence in the MRA ‐treated patients versus the control groups (15.0% versus 32.2%; odds ratio, 0.55; 95% CI , 0.44–0.70 [ P AF episodes ( odds ratio , 0.42; 95% CI , 0.31–0.59 [ P I 2 =54%; P =0.0008). Meta‐regression analyses showed that effect size was significantly associated with older studies and higher AF occurrence rate in the control groups. Conclusions MRA s seem to be effective in AF prevention, especially regarding recurrent AF episodes.

International audience; Since 2016, the French Society of Hypertension has warned about the decline in the management of high blood pressure in France: stagnation, or even decreased number of people who know their blood pressure level, take a treatment and are controlled. These results are lower than those observed in many other countries. Blood pressure is measured with an old method in the doctor's office. Accepted, simple and cost-effective, this method is currently unavoidable for reasons of feasibility and social habit. It has been used in observational and intervention studies that are the basis of the medical reasoning for screening, treatment and drug control of hypertension. In practice, it is too often poorly applied and unpredictable. It is now necessary to measure blood pressure in mmHg using a validated oscillometric automatic device coupled to a specific upper arm cuff adapted to the arm circumferences for the diagnosis and monitoring of high blood pressure in the doctor's office and at home. The auscultatoric measurement is only recommended if any doubt about the reliability of the electronic measurement. Blood pressure measurement is basically performed on both arms to detect asymmetry and then on the arm with the highest blood pressure. It is performed in sitting or lying position after a few minutes of rest without speaking and without having smoked and then in standing position to diagnose orthostatic hypotension, especially in elderly, diabetic and multi-medicated subjects. The blood pressure measurement during the consultation must be repeated and include at least 3 consecutive measurements at one minute intervals. The average of the last 2 measurements determines the blood pressure level. It is recommended to perform BP measurements outside the medical environment for the diagnosis and monitoring of hypertension; Home BP measurement is preferred to ambulatory blood pressure measurement for practical reasons unless otherwise specified. The home blood pressure measurement should include three measurements in the morning at breakfast and three measurements in the evening before bedtime at one minute intervals for at least three days. Prior training must be provided. In treated hypertensive patients, a masked hypertension should be considered as an uncontrolled hypertension and antihypertensive therapy adapted accordingly. The measurement of central BP pressure (aorta) should be limited to clinical research.

International audience; Therapeutic antibodies are increasingly used to treat various diseases, including neoplasms and chronic inflammatory diseases. Antibodies exhibit complex pharmacokinetic properties, notably owing to the influence of antigen mass, i.e. the amount of antigenic targets to which the monoclonal antibody binds specifically. This review focuses on the influence of antigen mass on the pharmacokinetics of therapeutic antibodies quantified by pharmacokinetic modelling in humans. Out of 159 pharmacokinetic studies, 85 reported an influence of antigen mass. This influence led to non-linear elimination decay in 50 publications, which was described using target-mediated drug disposition or derived models, as quasi-steady-state, irreversible binding and Michaelis-Menten models. In 35 publications, the pharmacokinetics was apparently linear and the influence of antigen mass was described as a covariate of pharmacokinetic parameters. If some reported covariates, such as the circulating antigen level or tumour size, are likely to be correlated to antigen mass, others, such as disease activity or disease type, may contain little information on the amount of antigenic targets. In some cases, antigen targets exist in different forms, notably in the circulation and expressed at the cell surface. The influence of antigen mass should be soundly described during the early clinical phases of drug development. To maximise therapeutic efficacy, sufficient antibody doses should be administered to ensure the saturation of antigen targets by therapeutic antibodies in all patients. If necessary, antigen mass should be taken into account in routine clinical practice.

ObjectiveTo identify patient characteristics associated with responsiveness to tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA).Materials and methodsIndividual patient data from 29 randomised controlled trials (RCTs) evaluating the efficacy of a TNFi versus placebo or conventional therapy were obtained. Response to treatment was assessed in subgroups according to the following baseline characteristics: smoking status, physical activity, sex, age, body mass index, autoantibody profile, disease duration, high initial disease activity defined by Disease Activity Score on 28 joints (DAS28)(C reactive protein (CRP)) >5.1. The primary outcome was the between-treatment group difference in DAS28(CRP) change from baseline to 6 months. The secondary endpoints were the between-treatment group difference in final DAS28(CRP) measured until 6 months and EULAR response criteria until 6 months. Data from each RCT were then pooled by the Mantel-Haenszel method using a random effects model. A linear metaregression was also carried out on two data-sharing platforms separately to support the results.ResultsIndividual data of 11 617 patients from 29 RCTs were analysed. Until 6 months, a significantly higher EULAR non-response rate was observed in obese patients (OR 0.52 vs 0.36 for non-obese, p=0.01). A multivariable regression model performed on 7457 patients indicated that patients treated by TNFi had a final DAS28(CRP) decreased by 0.02 for each year of disease duration (p5.1 (pConclusionsIn RA, patients who are more responsive to TNFi are those who are non-obese, have a long disease duration and have a high initial disease activity.

Background:TNF inhibitors have changed the course of rheumatoid arthritis (RA). Yet, detailed analysis on factors influencing clinical response to TNF inhibitors in RA is lacking.Objectives:Herein we aimed at studying the impact of demographics and disease-related factors on therapeutic response to golimumab and infliximab in RA.Methods:Randomized clinical trials (RCTs) that evaluated golimumab and infliximab versus placebo or conventional therapy were sought. We selected the following factors: age, sex, ethnicity, body mass index (BMI), smoking status, physical activity, disease duration, disease activity at baseline, presence of auto-antibodies. We studied the impact of these factors on clinical response using firstly aggregate data in a Mantel-Haenszel random effects model, and secondly individual data in a multivariate regression model.Results:Individual data from 8 RCTs, 2 on infliximab (n=1477) and 6 on golimumab (total =3041) were obtained. In the aggregate model analysis, none of the selected factors had a significant impact on clinical response. In the multivariate analysis, male sex and physical activity were significantly associated with a lower DAS28-CRP after 6 months of treatment (regression coefficients -0.264 (pConclusion:Male gender and practicing physical activity are associated with lower disease activity 6 months after golimumab or infliximab initiation. High baseline disease activity significantly influences negatively the effect of the treatment on disease activity score.Acknowledgements:This study, carried out under YODA Project 2018-2931, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C.Disclosure of Interests:Marc-Antoine SPARFEL: None declared, Sophie Derolez: None declared, Johan Law-Wan: None declared, Nicolas Azzopardi: None declared, Philippe Goupille Speakers bureau: Abbvie, Biogaran, BMS, Hospira, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB, Consultant of: Abbvie, Biogaran, BMS, Hospira, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB, Grant/research support from: Clinical trials sponsored by Abbvie, Roche, BMS, Boehringer, Lilly, Novartis, Pfizer, UCB, Janssen and MSD. Invitation to an international congresses by MSD, Roche, BMS and Abbvie, Denis Mulleman Speakers bureau: Pfizer and Novartis, Consultant of: Pfizer and Novartis, Grant/research support from: Invitation to an international congress by Janssen-Cilag, Theodora Bejan-Angoulvant: None declared

Aim: Eculizumab is a monoclonal antibody toward C5 fraction of the complement system. It is approved to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. To perform pharmacokinetic studies and therapeutic drug monitoring, a validated assay is required. Materials & methods: An indirect ELISA with recombinant human C5 sensitized microtiter plates were developed. Results: The assay allows the measurement of free eculizumab concentration in human serum. The LOD, LLOQ and ULOQ were 0.091, 0.25 and 82.35 mg/l, respectively. The assay meets EMA and US FDA guidelines criteria for the validation of a ligand-binding assay. Conclusion: This method is validated and can be used in PK and PK-PD studies as well as to perform therapeutic drug monitoring of free eculizumab.

Biopharmaceuticals, especially monoclonal antibodies, have been increasingly used to treat several chronic inflammatory diseases. Due to the complexity of their pharmacokinetics and concentration-effect relationship, therapeutic drug monitoring (TDM) has been used to optimize their dosing regimen. Up to date, several decisional algorithms have been developed to provide tools for monoclonal antibodies' therapeutic drug monitoring. However, these algorithms are unable to determine the individual optimal dosing scheme. The aim of this article is to deal with population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) modeling. Allowing the quantification of the variability of the dose-concentration-response relationship, population pharmacokinetic-pharmacodynamic modeling may be a valuable tool to determine the optimal dosing scheme. Based on population modeling, Bayesian estimators may be developed to optimize dosing schemes for each patient using limited sampling strategies. These estimators may allow accurate dosing adjustment for each patient individually.

This is the accepted version of the following article: "Rationale for Therapeutic Drug Monitoring of Biopharmaceuticals in Inflammatory Diseases", which has been published in final form at https://insights.ovid.com/crossref?an=00007691-201708000-00007; International audience; Biopharmaceuticals bring together a number of specific characteristics as compared with other drugs. However, as it is done for most drugs, an individual adjustment of their dose may be necessary. Similar to “chemical” drugs, biopharmaceuticals used in immunoinflammatory diseases have a rather narrow therapeutic range, lack good early clinical or biological marker of response, have variable pharmacokinetics, and their serum concentrations are most often related with response. Monoclonal antibodies have additional specific sources of pharmacokinetic variability. Low concentrations may increase the risks of immunization, plasmapheresis may increase their elimination, and subcutaneous formulations may be associated with decreased adherence. For all these reasons, pharmacokinetic therapeutic drug monitoring may be useful. However, few randomized controlled therapeutic drug monitoring studies have been published. For monoclonal antibodies, a precise definition of the therapeutic concentrations is challenging because of the interindividual variability in their concentration–effect relationship.

Aims Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients. Methods In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area (BSA), sex, and disease activity score in 28 joints (DAS28) on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis. Results A two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment (Vc) and clearance (CL) of rituximab were estimated at 4.7 L and 0.56 L/day, respectively. Distribution (T½-α) and elimination (T½-β) half-lives were 0.9 days and 17.3 days, respectively. As expected, the central volume of distribution increased with BSA (p = 0.012) and was higher in male than in female (p = 0.004). We found that the elimination rate constant (k10) increased with CD19+ count (p = 0.00022) and IgG concentration (p = 7.4 10-8), and that k10 decreased with time (p = 0.00015), partly explained by a change in target-antigen amount. Conclusions The association between CD19+ count and k10 may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k10 may be explained by a saturation of the neonatal Fc receptor (FcRn) at high IgG concentrations, resulting in decreased recycling of rituximab.

SummaryThe safety of dabigatran versus adjusted-dose vitamin K antagonist (VKA) treatment is the subject of debate. We evaluated the risk of myocardial infarction (MI) or mortality in patients with atrial fibrillation (AF) treated in clinical practice with dabigatran or a VKA. We performed a meta-analysis of observational studies that included an adjusted or matched analysis and reported MI, or death in AF patients treated with dabigatran or a VKA. Ten published analyses met the inclusion criteria. Of the 539,559 patients, 17,365 (3%) patients were on dabigatran 110 mg twice daily (bid), 150,948 (28%) were on dabigatran 150 mg bid, and 371,246 (69%) were on VKA. Adjusted risk for MI versus VKA was 0.71 (0.47–1.07; p=0.10) in patients starting oral anticoagulant (OAC) treatment with dabigatran 110 mg, 0.82 (0.71–0.96; p=0.01) in patients starting dabigatran 150 mg, 1.40 (1.04–1.88; p=0.03) in patients switching OAC treatment to dabigatran 110 mg, and 1.28 (0.88–1.87; p=0.19) in patients switching OAC treatment to dabigatran 150 mg, with statistical homogeneity in each subgroup. Risk of death was consistently lower in patients treated with dabigatran 110 mg (HR 0.79; 0.65–0.96; p=0.02) or 150 mg (HR 0.65; 0.57–0.73; p

Background: Plasma creatinine has been described as a prognostic biomarker for Amyotrophic Lateral Sclerosis (ALS), but with conflicting results in the literature. We performed a systematic review ...

BackgroundThe last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality.Methods and findingsWe conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level.ConclusionsSGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention.Trial registrationPROSPERO CRD42016043823.

International audience; AIM: Recent US recommendations indicate a target blood pressure (BP) of 130/80mmHg for patients with type 2 diabetes (T2D). Our aim was to characterize the association between risk of cardiovascular events and differences in BP decreases in randomized trials of a T2D population. METHODS: A systematic search was made for randomized clinical trials assessing the effects of antihypertensive treatments in T2D patients on mortality, and fatal and non-fatal cardiovascular events, using a meta-regression technique to explore the influence of BP decreases on treatment effects. RESULTS: A total of 88,503 patients from 44 randomized trials were included. There was no significant association between BP decreases and risk of all-cause or cardiovascular mortality, cardiovascular events or myocardial infarction. However, stroke risk was influenced by BP decreases: compared with no reduction, a 10-mmHg reduction in systolic BP was associated with a relative odds ratio (OR) decrease of 33% (OR: 0.67, 95% CI: 0.54-0.82), and a 5-mmHg diastolic BP reduction was associated with a relative OR decrease of 38% (OR: 0.62, 95% CI: 0.50-0.76). Restricting the analysis to double-blind studies did not change the results for diastolic BP. CONCLUSION: A reduction in BP lowers the risk of stroke, but does not appear to affect the risk of other cardiovascular events in a T2D population.

Therapie - Sous presse. Epreuves corrigees par l'auteur. Disponible en ligne depuis le jeudi 25 aout 2016

Background Infarct size, a key prognostic factor in ST-segment elevation myocardial infarction (STEMI), is best assessed by late gadolinium enhancement in cardiac magnetic resonance imaging (MRI). MRI availability being limited, necrosis biomarkers (peak concentration and/or area under the concentration versus time curve (AUC)) are used as surrogate markers of infarct size. These methods, excluding biomarkers kinetic data, may provide inaccurate results. We recently developed and published about compartmental kinetic models allowing estimation of the total amount of necrosis biomarker released in STEMI, A0, with reduced blood sampling. Purpose We sought to evaluate the correlation between A0 of necrosis biomarkers and MRI measurements of infarct size in STEMI patients. Methods We retrospectively included all STEMI patients with timely reperfusion and a cardiac MRI in the early recovery period in Tours University Hospital (France) from February 2015 to September 2017. Kinetics of Creatine kinase (CK), troponin I (cTnI) and/or T (cTnT), were described using our models and we compared the maximum concentration (Cmax), estimated AUC and A0 to MRI measurements of infarct size. Results Forty-one patients were included; all had CK assays, 16 had cTnI assays and 25 hs-cTnT assays. Our population had similar characteristics to the STEMI population reported in the latest FAST-MI registry. The models described satisfactorily biomarker kinetic data. Infarct size was correlated with all CK and hs-cTnT parameters, particularly cTnT A0 (R2 = 67,1%) and CK Cmax (R2 = 64,8%). The correlation was lower with cTnI parameters ( Fig. 1 ). Conclusion Our models described accurately necrosis biomarkers kinetics following STEMI. The total amount of hs-cTnT released and estimated CK peak concentration were best correlated to MRI infarct size and may be used as easy and accurate estimators of infarct size. This method may be a major advance for future clinical trials on cardioprotection.

Immunotherapy medications that target programmed death 1 protein (PD-1) and programmed death-ligand 1 (PD-L1), such as nivolumab, pembrolizumab, and atezolizumab, are currently used in the first- or second-line treatment of non-small cell lung cancers, among other indications. However, these agents are associated with immune-related side effects, the most common of which are endocrinopathies, colitis, hepatitis, and interstitial pneumonitis. In contrast, coronary toxicities are rarely reported and remain poorly understood. Here, we describe the case of a patient who developed an acute coronary syndrome when treated with nivolumab as second-line therapy for metastatic pulmonary adenocarcinoma. A review of the literature, the French pharmacovigilance registry, and the World Health Organization pharmacovigilance database led to the identification of four cases of patients with coronary manifestations attributable to anti-PD1 immunotherapy (with no reported cases of patients undergoing anti-PD-L1 immunotherapy), which we describe herein. The potential mechanisms causing adverse coronary reactions to this type of therapy, which is used to treat lung cancer as well as other solid and hematological neoplastic diseases, are also discussed.

International audience; Purpose: Trastuzumab is the most widely prescribed anti-HER2 humanized monoclonal antibody. Cardiac toxicity is the only limiting toxicity of trastuzumab and it is of particular concern in patients with complete response, since the drug needs to be stopped, with a risk of disease relapse. To date, no pharmacological data on trastuzumab cardiotoxicity in patients have been made available. Here, we provide proof of concept, demonstrating that it was possible to prevent trastuzumab-induced cardiotoxicity by modifying the drug administration schedule.Methods: In this paper, we report the case of a patient with metastatic breast cancer responding to trastuzumab, who developed severe cardiac toxicity twice using a 3-weekly regimen. Considering preclinical pharmacological data on trastuzumab cardiotoxicity, we hypothesized that a weekly schedule of trastuzumab with lower peaks of serum concentration could be safe while remaining efficient. With the patient's consent, we started a weekly combination of carboplatin (AUC2) and trastuzumab (2 mg/kg) with close monitoring of trastuzumab concentrations.Results: We successfully controlled the disease for an additional 6 months with relevant trough concentrations of trastuzumab of around 50 mg/L. Another important aspect is that, with this weekly schedule, we observed no cardiac toxicity, and the left ventricular ejection fraction remained stabilized, at over 50%.Conclusions: Trastuzumab is the most widely prescribed anti-HER2 monoclonal antibody for the treatment of HER2 metastatic breast cancer, and it is the only drug that has been approved for the treatment of localized HER2 breast cancer, 1-year treatment being required after surgery. In case of cardiac toxicity, particularly in women over 60 years of age, a weekly regimen with lower peaks of concentration could be an alternative to the standard 3-weekly regimen.

Introduction Les immunotherapies ciblant le PD-1 ou PD-L1 sont associees a divers effets indesirables immunologiques (endocrinopathies, hepatites, pneumonies interstitielles). En revanche, les toxicites coronariennes sont rarement rapportees et peu comprises. Nous decrivons le cas d’une patiente ayant presente un syndrome coronarien aigu en cours de traitement par nivolumab pour un adenocarcinome pulmonaire. Trois cas de toxicites coronariennes issus de la litterature ou des registres de pharmacovigilance sont rapportes ainsi que les mecanismes physiopathologiques envisageables. Methodes Nous avons interroge les bases de donnees PubMed, de pharmacovigilance francaise et de l’OMS. Resultats Nous rapportons le cas d’une patiente de 60 ans, fumeuse active a 30 paquets-annees, en 2e ligne de traitement par nivolumab pour un adenocarcinome pulmonaire classe T4N3M1b, sans addiction oncogenique. Elle a presente, durant la 2e administration de nivolumab, une douleur thoracique, avec sus-decalage ST anterieur et elevation du taux de troponine. La coronarographie, realisee trois heures apres l’arret de la douleur, ne retrouvait pas de stenose significative. L’IRM myocardique, realise trois jours apres l’episode, montrait un œdeme antero-septal. L’etiologie la plus probable etait donc un vasospasme coronaire dans le territoire de l’artere coronaire interventriculaire anterieure. Trois autres cas ont donc pu etre identifies dans les bases de donnees utilisees ( Tableau 1 ). Differents mecanismes pouvant expliquer des vasospasmes coronaires sous immunotherapie peuvent etre envisages comme une toxicite directe de l’inhibition de PD-1 sur les cellules cardiaques, un mecanisme d’hypersensibilite, une modification de l’environnement cytokinique ou encore une destabilisation de plaques coronaires non detectables en coronarographie. Conclusion Meme si les toxicites coronariennes des anti-PD-1 et anti-PD-L1 sont rares, il semble important d’alerter les cliniciens sur leur existence du fait de consequences potentiellement severes. La mise en place de recommandations quant a leur detection et prise en charge parait indispensable actuellement avec la multiplication des indications de ces traitements.

Infarct size is a major predictor of subsequent cardiovascular events following ST-segment elevation myocardial infarction (STEMI) and is frequently used in clinical trials focused on cardioprotection. Approximately assessed through serial blood sampling, it can be accurately measured by imaging techniques, e.g. cardiac magnetic resonance imaging, which is the actual gold standard for infarct size determination but with limited availability in daily practice. We developed a mathematical biomarker kinetic model based on pharmacokinetic compartment models to easily and accurately estimate infarct size using individual data from five clinical trials evaluating the impact of conditioning therapies in STEMI between 2005 and 2013. Serial blood sampling was available in all studies with data regarding creatine kinase (CK), CK specific of cardiomyocytes (CK-MB) and cardiac troponin I. Our model allowed an accurate estimation of biomarker release as a surrogate marker of infarct size and a powerful assessment of conditioning treatments. This biomarker kinetic modelling approach identified CK-MB as the most accurate biomarker in determining infarct size and supports the development of limited sampling strategies that estimate total biomarker amount released with a lower number of samples. It will certainly be a useful add-on to future studies in the field of STEMI and cardioprotection.

BACKGROUND Active smoking is associated with elevated thrombotic risk. Smoking status has recently been incorporated into the SAMe-TT2R2 (sex female, age METHODS We examined the clinical course of 7, 809 consecutive patients with AF seen between 2000 and 2010. Outcomes in patients who were active smokers were compared with those in other patients. RESULTS Among 7, 809 patients with AF, 1, 034 (13%) were active smokers. APT was prescribed on an individual basis for 2, 761 patients (35%) and VKAs for 4, 534 (57%). After a follow-up of 929 ± 1, 082 days (median = 463 days, interquartile range = 1,564 days), smoking was not independently associated with a higher risk of stroke/thromboembolic event in patients with AF (hazard ratio [HR], 0. 95;95% CI, 0. 78-1. 22; P =.66). On multivariate analysis, smoking was independently associated with a worse prognosis for the risk of severe bleeding (HR, 1. 23;95% CI, 1. 01-1. 49; P =. 04) and for the risk of major Bleeding Academic Research Consortium bleeding (HR, 1. 40;95% CI, 1. 02-1. 90; P = .03). Smoking was independently associated with a higher risk of bleeding in patients treated with VKAs (HR, 1. 32;95% CI, 1. 04-1. 67; P = .02), whereas the risk was nonsignificant in patients treated with APT (HR, 1. 28;95% CI, 0. 94-1. 74; P = .11). CONCLUSIONS In AF, there was a higher risk of severe bleeding in smokers, mainly in those treated with VKAs.

Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.

Recent recommendations regarding type 2 diabetes (T2D) patients' treatments have focused on personalizing glycosylated haemoglobin (HbA1c) targets. Because the relationship between HbA1c and diabetes prognosis has been established from large prospective cohorts, it is valid to question the extrapolation from population-based risk reduction estimations to individual predictions. Our study aimed to investigate the relationship between HbA1c reductions and clinical outcomes in randomized controlled trials (RCTs), using a meta-regression approach. Included were RCTs comparing intensive vs. standard glucose-lowering regimens for cardiovascular events and microvascular complications in T2D patients. Eight studies (33,396 patients) providing data for HbA1c reductions were found. In our meta-regression, HbA1c decreases were not significantly associated with reductions in our main study outcomes: total and cardiovascular mortality. They were also not associated with any of the secondary endpoints, including myocardial infarction, stroke and severe hypoglycaemia. Sensitivity analysis showed a significant correlation only between HbA1c-lowering and severe hypoglycaemia (P = 0.014). Meta-regression analysis could find no significant association between HbA1c-lowering and a decrease in clinical outcomes, thereby questioning the use of HbA1c as a surrogate outcome for T2D-related complications. Thus, RCTs vs. placebo are urgently required to evaluate the risk-benefit ratios of therapeutic strategies beyond HbA1c control in T2D patients.