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Alirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic-pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations.Using data collected from nine phase I/II/III clinical studies (n = 527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling. A "full fixed effects modeling" strategy was implemented to quantify parameter-covariate relationships.The model captures the interaction between alirocumab and its target PCSK9 and how this mechanism drives LDL-C depletion, with an estimation of the associated between-subject variability of model parameters and the quantification of clinically relevant parameter-covariate relationships. Co-administration of statins was found to increase the central volume of distribution of alirocumab by 1.75-fold (5.6 L versus 3.2 L) and allow for a 14% greater maximum lipid-lowering effect (88% versus 74%), highlighting the synergy of action between anti-PCSK9 therapeutic antibodies and statins toward lowering LDL-C plasma levels. Baseline levels of PCSK9 were found to be related to the amplitude of LDL-C variations by increasing the concentration of free PCSK9 necessary to reach half its capacity of inhibition of LDL-C degradation.The maximum effect of alirocumab is achieved when free PCSK9 concentration is close to zero, as seen mostly after 150 mg every 2 weeks (Q2W) or 300 mg every 4 weeks (Q4W), indicating that there would be no additional clinical benefit of increasing the dose higher than these recommended dosing regimens.

Abnormal elevation of thyroid antibodies in the CSF is observed in 62-75% of Hashimoto's encephalopathy cases. However, the relationship between CSF thyroid antibody levels and response to therapy has been poorly evaluated. We report the case of a 68-year-old man with Hashimoto's encephalopathy, in whom there was a relation between the favorable clinical outcome and the disappearance of antithyroid antibodies from the CSF and a decrease in serum thyroid antibodies.Une élévation anormale des anticorps thyroïdiens dans le LCR est observée dans 62 à 75 % des cas d’encéphalopathie de Hashimoto. Cependant, la relation entre les niveaux d’anticorps thyroïdiens dans le LCR et la réponse au traitement a été rarement évaluée. Nous rapportons le cas d’un homme de 68 ans atteint d’encéphalopathie de Hashimoto, chez qui l’évolution clinique favorable sous traitement était associée à la disparition des anticorps antithyroïdiens du LCR et une diminution des anticorps thyroïdiens sériques.

Background The ODYSSEY CHOICE I study (NCT01926782) evaluated alirocumab 300 mg every 4 weeks (Q4W) in patients with hypercholesterolemia receiving maximally tolerated statin or no statin. Objective The objective of the study was to assess the relationship between alirocumab, proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein cholesterol (LDL-C) concentrations with the CHOICE I alirocumab dosing regimen. Methods This analysis included 803 patients (547 statin-treated, 256 without statin) who were randomized to alirocumab 300 mg Q4W, alirocumab 75 mg every 2 weeks (Q2W), or placebo. 300 mg Q4W and 75 mg Q2W doses were adjusted to 150 mg Q2W at Week 12 if Week 8 LDL-C was >70 or >100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was Results Most patients remained on 300 mg Q4W without dose adjustment as they achieved study-defined LDL-C goals at Week 8 (statin-treated: 80.7%; no statin: 85.3%). LDL-C was reduced by 60.5%–71.9% over Weeks 20–24 in patients on 300 mg Q4W and 57.2%–63.0% in patients with dose adjustment from 300 mg Q4W to 150 mg Q2W. Statin-treated patients had higher cardiovascular risk as well as higher free PCSK9 and lower alirocumab concentrations (vs no statin), suggesting increased target-mediated clearance. Regardless of statin status, the most common adverse events in alirocumab-treated patients were injection-site reaction and headache. Conclusions Data provide further insight on alirocumab's mode of action in terms of relationship between alirocumab, PCSK9, and LDL-C, and disease severity, and support the use of alirocumab 300 mg Q4W as an efficacious dosing regimen for clinically meaningful LDL-C reductions.

We reported two cases of Staphylococcus aureus Infective Endocarditis associated with vasculitides and glomerulonephritis respectively, before conducting an online search of previously published similar cases reports. Twenty five references were selected: 15 cases of glomerulonephritis; 2 cases of vasculitis and 8 cases involving both glomerulonephritis and vasculitis. Vasculitides and glomerulonephritis associated with Staphylococcus aureus definite Infective Endocarditis have been reported since 1976. All cases except one described clinical symptoms occurring before or during initial antibiotics treatment. Except kidney, organs that were more frequently affected by vasculitis process were skin, gastrointestinal tract and peripheral nerve and the vessels involved were small to medium size vessels. When antineutrophil cytoplasmic antibodies were evidenced (6 out of the 25 cases (24%)), kidney was the most frequently affected organ. The most commonly observed pattern in Kidney biopsy was membranoproliferative glomerulonephritis with endocapillary proliferation sometimes associated with extra capillary crescents, whether or not antineutrophil cytoplasmic antibodies were evidenced. Right-sided Infective Endocarditis (especially in intravenous drug users) were overrepresented (14 of the 25 cases (56.0%)) in this review. Besides antibiotics, corticosteroids were the most frequently prescribed immunosuppressive treatment both for vasculitides or glomerulonephritis. KEY MESSAGES Vasculitides and glomerulonephritis associated with Staphylococcus aureus definite Infective Endocarditis have been reported since 1976. Except kidney, organs that were more frequently affected (by small to medium size vessel vasculitis) were skin, gastrointestinal tract and peripheral nerve. The most commonly observed pattern in Kidney biopsy was membranoproliferative glomerulonephritis with endocapillary proliferation and right-sided Infective Endocarditis (especially in intravenous drug users) were overrepresented in this review.

Aurélie Brunet,1 Yohan N’Guyen,1,* Annick Lefebvre,2,* Anne Poncet,3 Ailsa Robbins,1 Odile Bajolet,2 Yves Saade,3 Vito Giovanni Ruggieri,3,* Sylvain Rubin3,* 1Internal Medicine, Infectious Diseases and Clinical Immunology, Robert Debré University Hospital, Reims, France; 2Operational Hygiene Team, Robert Debré University Hospital, Reims, France; 3Thoracic and Cardiovascular Surgery, Robert Debré University Hospital, Reims, France*These authors contributed equally to this workCorrespondence: Yohan N’GuyenInternal Medicine, Infectious Diseases and Clinical Immunology, Robert Debré University Hospital, Avenue du général Koenig, Reims 51092, FranceTel (+33) 3 26 78 94 22Fax (+33) 3 26 78 40 90Email yohan.nguyen@wanadoo.frPurpose: Obesity remains statistically associated with coronary artery disease, for which coronary artery bypass graft surgery (CABG) remains the standard of care. However, obesity is also associated with sternal wound infection (SWI) which is a severe complication of CABG despite advances in surgery and in infection prevention and control. Strategies to reduce the incidence of SWI are still being investigated, and we therefore conducted a retrospective study to revisit factors other than obesity associated with SWI after CABG.Patients and Methods: Data were extracted from the medical records of 182 patients who underwent elective on-pump CABG using one or both pedicled internal mammary artery grafts in Reims University Hospital between May 2015 and May 2016. All preoperative or perioperative variables with a p value< 0.10 in univariate analysis were entered into a stepwise logistic regression model.Results: Among the 182 patients (145 male (79.6%), median age 68.0 [45.0– 87.0] years), 138 (75.8%) underwent CABG using bilateral internal mammary artery grafts. Median BMI was 27.7 [18.7– 50.5] kg/m2, and there were 51 (28.0%) and 79 (43.4%) patients with obesity and overweight, respectively. Twenty-three out of the 182 patients (12.6%) developed SWI. In-hospital mortality was not statistically different between patients with and without SWI but the median length of stay was (6.0 [2.0– 38.0] versus 5.0[3.0– 21.0] days in the intensive care unit, p=0.03, and 26.0 [9.0– 134.0] versus 9.0 [7.0– 51.0] days in hospital, p< 0.0001). Obesity and preoperative anaemia were independently associated with SWI, as was the number of red blood cell (RBC) units transfused (OR 14.61 [2.64– 80.75], OR 4.64 [1.61– 13.34] and OR 1.27 [1.02– 1.58], respectively).Conclusion: The independent association of SWI with the number of RBC units transfused and the existence of preoperative anaemia and obesity suggests a mechanism of thoracic wall ischemia in SWI after CABG, thus leaving insufficient perfusion of the thoracic wall in patients with obesity. Medical strategies are warranted to try to prevent this costly complication.Keywords: obesity, preoperative anaemia, coronary artery bypass graft surgery, internal mammary arteries

Background Alirocumab, a human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to significantly reduce low-density lipoprotein cholesterol levels; pharmacokinetics (PK) are governed by non-linear, target-mediated drug disposition (TMDD). Objectives We aimed to develop and qualify a population PK (PopPK) model to characterize the PK profile of alirocumab, evaluate the impact of covariates on alirocumab PK and on individual patient exposures, and estimate individual predicted concentrations for a subsequent PK/pharmacodynamic (PD) analysis. Methods Data from 13 phase I–III trials of 2799 healthy volunteers or patients with hypercholesterolemia treated with intravenous or subcutaneous alirocumab (13,717 alirocumab concentrations) were included; a Michaelis–Menten approximation of the TMDD model was used to estimate PK parameters and exposures. The final model comprised two compartments with first-order absorption. Elimination from the central compartment was described by linear (CLL) and non-linear Michaelis–Menten clearance (Vm and Km). The model was validated using visual predictive check and bootstrap methods. Patient exposures to alirocumab were computed using individual PK parameters. Results The PopPK model was well-qualified, with the majority of observed alirocumab concentrations in the 2.5th–97.5th predicted percentiles. Covariates responsible for interindividual variability were identified. Body weight and concomitant statin administration impacted CLL, whereas time-varying free PCSK9 concentrations and age affected Km and peripheral distribution volume (V3), respectively. No covariates were clinically meaningful, therefore no dose adjustments were needed. Conclusions The model explained the between-subject variability, quantified the impact of covariates, and, finally, predicted alirocumab concentrations (subsequently used in a PopPK/PD model, see Part II) and individual exposures. Electronic supplementary material The online version of this article (10.1007/s40262-018-0669-y) contains supplementary material, which is available to authorized users.

Background Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. Objective This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. Methods From a dataset of 2799 individuals (14,346 low-density lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing low-density lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. Results The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual low-density lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in low-density lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain between-subject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. Conclusions This model successfully allowed the characterization of the population pharmacokinetic/pharmacodynamic properties of alirocumab in its target population and the estimation of individual low-density lipoprotein cholesterol levels. Electronic supplementary material The online version of this article (10.1007/s40262-018-0670-5) contains supplementary material, which is available to authorized users.

BACKGROUND: Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). METHODS: Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W. RESULTS: Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. CONCLUSIONS: Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production. (C) 2019 National Lipid Association. Published by Elsevier Inc.

Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C).This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients.HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8.Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events.In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.

A Phase 2 dose-finding study ([NCT02890992][1]) evaluated the efficacy, safety, and dose selection of the PCSK9 inhibitor alirocumab in pediatric patients with heterozygous familial hypercholesterolemia (HeFH). Patients (N=42) aged 8–17 years, with body weight ≥25 kg and with HeFH and LDL-C ≥

Delayed onset haemolysis occurring post-artesunate and post-artemisinin combination therapy is secondary to delayed clearance of infected erythrocytes spared by pitting during treatment. We report a case of severe post-treatment delayed haemolytic anaemia with a positive direct antiglobulin test and a positive response to corticosteroid therapy, suggesting an associated immune mechanism.

Background and Objective Proprotein convertase subtilisin/kexin type 9 inhibition with monoclonal antibodies such as alirocumab significantly reduces low-density lipoprotein-cholesterol levels ± other lipid-lowering therapies. We aimed to develop and qualify a population pharmacokinetics (PopPK) model for alirocumab in healthy subjects and patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. Methods This TMDD model was developed using a subset of the alirocumab clinical trial database, including nine phase I/II/III studies (n = 527); the model was subsequently expanded to a larger data set of 13 studies (n = 2870). Potential model parameters and covariate relationships were explored, and predictive ability was qualified using a visual predictive check. Results The TMDD model was built using the quasi-steady-state approximation. The final TMDD–quasi-steady-state model included a significant relationship between distribution volume of the central compartment and disease state: distribution volume of the central compartment was 1.56-fold higher in patients vs. healthy subjects. Separately, application of the model to the expanded data set revealed a significant relationship between linear clearance and statin co-administration: linear clearance was 1.27-fold higher with statins. The good predictive performance of the TMDD model was assessed based on graphical and numerical quality criteria, together with the visual predictive check and comparison of the predictions to those from a PopPK model with parallel linear and Michaelis–Menten clearances (i.e., simplification of the TMDD PopPK model). Conclusions This mechanistic TMDD PopPK model integrates the interaction of alirocumab with its target and accurately predicts both alirocumab and total proprotein convertase subtilisin/kexin type 9 concentrations in healthy subjects and patients. Electronic supplementary material The online version of this article (doi:10.1007/s40262-016-0505-1) contains supplementary material, which is available to authorized users.

In 10 clinical trials involving 4747 patients, among those who received the PCSK9 inhibitor alirocumab, antidrug antibodies developed in 5.1%, although no significant effect was seen on the reduction in LDL cholesterol levels.

Background Alirocumab undergoes target‐mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 ( PCSK 9). Statins increase PCSK 9 levels; the effects of nonstatin lipid‐lowering therapies are unclear. Every‐4‐weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved. Methods and Results Low‐density lipoprotein cholesterol ( LDL ‐C), PCSK 9, and alirocumab levels were assessed in subjects ( LDL ‐C >130 mg/dL, n=24/group) after a 4‐week run‐in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL ‐C reductions from day −1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL ‐C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK 9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK 9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo. Conclusions Alirocumab 150 mg every 4 weeks produced maximal LDL ‐C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid‐lowering therapies appear to increase PCSK 9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid‐lowering therapies concomitantly. Clinical Trial Registration URL : http://www.Clinicaltrials.gov . Unique identifier: NCT 01723735.

Graphical abstract, Diacetate protection of 5 and 6-carboxyfluorescein followed by synthesis of the N-hydroxysuccinimide esters allowed ready separation of the two isomers on a multi-gram scale. The 5 and 6-carboxyrhodamine B N-hydroxysuccinimide esters were also readily synthesised and separated.

With the aim of developing new SPECT imaging agents for the translocator protein (TSPO), a small library of iodinated quinoline-2-carboxamides have been prepared and tested for binding affinity with TSPO. N,N-Diethyl-3-iodomethyl-4-phenylquinoline-2-carboxamide was found to have excellent affinity (Ki 12.0 nM), comparable to that of the widely used TSPO imaging agent PK11195.