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To assess a model combining OCT angiography (OCTA) and OCT parameters to predict the severity of paracentral visual field (VF) loss in primary open-angle glaucoma (POAG).Cross-sectional study.Forty-four patients with POAG and 42 control subjects underwent OCTA and OCT imaging with a swept-source OCT device.The circumpapillary microvasculature was quantified for vessel density (cpVD) and flow (cpFlow) after delineation of Bruch's membrane opening and removal of large vessels. Retinal nerve fiber layer thickness (RNFLT) and Bruch's membrane opening-minimum rim width (BMO-MRW) were measured from structural OCT. Paracentral total deviation (PaTD) was defined as the average of the total deviation values within the central 10 degrees on Humphrey VF testing (24-2) for upper and lower hemifields. The OCT and OCTA parameters were measured in the affected hemisphere corresponding to the hemifield with lower PaTD for POAG patients. Models were created to predict affected PaTD based on RNFLT alone; RNFLT and BMO-MRW; OCTA alone; or RNFLT, BMO-MRW and OCTA parameters. The models were compared using coefficient of determination (rPerformance of models containing OCT and OCTA parameters in predicting PaTD.Patients with POAG and controls were similar in age and sex (65.9 ± 9.5 years and 38.4% male overall, P ≥ 0.56 for both). Average RNFLT, minimum RNFLT, average BMO-MRW, minimum BMO-MRW, cpVD, and cpFlow were all significantly lower (all P0.001) in the affected hemisphere in patients with POAG than in controls. In patients with POAG, the average mean deviation was -4.33 ± 3.25 dB; the PaTD of the affected hemifield averaged -4.55 ± 5.26 dB and correlated significantly with both OCTA and structural OCT parameters (r ≥ 0.43, P ≤ 0.004 for all). The model containing RNFLT, BMO-MRW, and OCTA parameters was superior in predicting affected PaTD (rA combined model of OCTA and structural OCT parameters can predict the severity of paracentral VF loss of the affected hemifield, supporting clinical utility of OCTA in patients with POAG with paracentral VF loss.

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses.

Patients with moderate to severe allergic rhinitis may benefit from subcutaneous immunotherapy (SCIT), despite the risk of systemic allergic reaction. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin (IL)-4 and IL-13, key drivers of the type 2 inflammation seen in allergic rhinitis, thereby inhibiting their signaling. In the LIBERTY Grass AID trial (NCT03558997), 16 weeks of treatment with 300 mg dupilumab every 2 weeks plus Timothy grass (TG) SCIT did not reduce TG allergen challenge nasal symptom scores compared with SCIT only but did improve tolerability of SCIT up-titration in patients with a history of grass pollen-induced seasonal allergic rhinitis. Here we present the pharmacokinetics of functional serum dupilumab and concentration-response relationships in 52 patients enrolled in this trial. Functional dupilumab concentrations and concentrations of TG-specific immunoglobulin E (IgE) and IgG4 were assessed in blood samples collected from dupilumab-only and SCIT+dupilumab-treated groups. Mean functional dupilumab concentrations were similar in both groups and reached a steady state of approximately 70-80 mg/L at week 5. One week after the end of treatment, TG-specific IgG4 concentrations were increased in the SCIT+dupilumab group, but not in the dupilumab-only group, over the range of dupilumab concentrations evaluated, whereas no changes were seen for TG-specific IgE concentrations. This study demonstrates that SCIT does not alter functional concentrations of serum dupilumab, and the impact of SCIT on TG-specific immunoglobulins is not affected by functional dupilumab concentrations over the range studied, indicating that maximum response was achieved in all patients. This article is protected by copyright. All rights reserved.

This retrospective review of 7 cases demonstrates that endoscopic cyclophotocoagulation via eyelid incision and enlargement of pars plana vitrectomy entry sites can lower intraocular pressure in eyes with history of Boston keratoprosthesis Type II surgery.

Objectives To describe the immunogenicity profile of sarilumab in Japanese patients with rheumatoid arthritis (RA). Methods Patients enrolled in the KAKEHASI and HARUKA studies were included in our analysis. In these studies, patients received sarilumab 150 mg or 200 mg every 2 weeks for 52 or 28 weeks in combination with methotrexate (MTX) (KAKEHASI), or for 52 weeks as monotherapy or in combination with non-MTX conventional synthetic disease-modifying anti-rheumatic drugs (HARUKA). Anti-drug antibodies (ADAs) and neutralising antibodies (NAbs) were assessed in the pooled population. Results Positive ADA assay responses occurred in 10/149 (7.1%) patients treated with sarilumab 150 mg and 13/185 (7.0%) patients treated with sarilumab 200 mg, with persistent responses in 2 (1.4%) and 4 (2.2%) patients, respectively. Peak ADA titre was 30. No patients treated with the 150 mg dose and one patient (0.5%) treated with the 200 mg dose exhibited NAbs. There was no evidence of an association between ADA formation and hypersensitivity reactions or reduced efficacy. Conclusions ADAs, which occurred at a low frequency and titre, did not affect the safety or efficacy of sarilumab 150 or 200 mg administered as monotherapy or combination therapy in Japanese patients with RA in the KAKEHASI or HARUKA studies.

A population pharmacokinetic model was developed using data from healthy subjects and patients with moderate‐to‐severe asthma receiving intravenous or subcutaneous dupilumab doses. A total of nine phase I to phase III studies were pooled (202 healthy subjects and 1912 patients with asthma including 68 adolescents) in the model development. The best model was a two‐compartment model with parallel linear and nonlinear Michaelis–Menten elimination with first order absorption. The PK parameter estimates were distribution volume of central compartment 2.76 L, linear elimination rate 0.0418 1/day, and subcutaneous bioavailability 60.9%. Pharmacokinetics (PK) properties of dupilumab in patients with asthma were determined to be comparable to those of healthy subjects and patients with atopic dermatitis. Only body weight exerts a notable effect explaining between‐subject variability in dupilumab PK, but dose adjustment for weight is not warranted based on results from clinical studies. There is no PK difference between adolescent and adult patients with asthma after correction for body weight.

Population pharmacokinetic (PK) base and covariate analyses were conducted using data from adolescents with moderate‐to‐severe atopic dermatitis (AD) and children ≥6 to

We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6–mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.

Patients with cancer often experience multiple symptoms concurrently. We identified patient clusters based on longitudinal symptom severity trajectories in oropharyngeal cancer (OPC) and evaluated the potential clinical utility of this approach.A retrospective OPC patient cluster analysis using 6 months of symptom severity data from radiotherapy initiation. The clinico-demographic characteristics and overall survival of patients were compared between clusters.We identified four clusters of patients differing in longitudinal symptom severity. Cluster A (n = 168) included patients with the mildest longitudinal symptoms, cluster B (n = 59) and cluster C (n = 63) were intermediate, and cluster D (n = 30) included patients with the worst symptoms. The clusters differed in their HPV status, ECOG performance status, smoking history, drinking history, treatment modality, and 5-year survival. These clusters separated symptom severity trajectories more distinctly than individual clinico-demographic characteristics.Early symptom severity trajectory clustering revealed distinct patient clusters that were prognostic of overall survival.

The eye and the kidney share structural and developmental similarities on a cellular and clinical level, and they are often affected by the same disease processes. Performing an eye exam to look for signs of conditions such as hypertension and diabetes can provide a helpful window into the health of the kidney. Patients with kidney transplants (KT) are a unique population that require close monitoring. These patients are maintained on a number of immunosuppressive medications and may face complications such as medication side effects, infections, and graft rejection. Patients with KT are at higher risk of both infectious and noninfectious eye conditions related to underlying systemic disease or use of immunosuppressive medications. Screening for eye conditions is important because preserving visual function is integral to quality of life, and also because the eye exam can help with early detection and treatment of systemic conditions. Here we describe some of the common eye findings and conditions in patients with KT. We recommend that patients with KT receive annual eye exams, and we hope that the information provided here can help nephrologists become more familiar with eye findings and identify situations where a referral to ophthalmology is warranted.

Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project. Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters. On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise. QC 20200930

Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity. Six healthy males received a single oral dose of 200 mg [14C]-fedratinib base (2.775 MBq, 75 μCi) as a solution. Blood, urine and feces samples were collected for up to 35 day postdose. Urine and feces samples were collected until the 24-h excretion of radioactivity fell below 0.5% of administered dose (at least 14 day postdose). Expired air was collected up to 8-h postdose. Total radioactivity (blood, plasma, urine, feces, and expired air) and fedratinib concentrations (plasma) were measured. Approximately 77% (23% unchanged) of fedratinib derived radioactivity was excreted in feces and 5% (3% unchanged) was excreted in urine. Excretion via expired air was negligible. The time to maximum concentration for both total radioactivity and parent drug was similar, with unchanged drug representing the majority of the circulating radioactivity. The ratio of blood to plasma concentration of radioactivity ranged from 0.615 to 0.753 indicating limited distribution of fedratinib and/or its metabolites into red blood cells. Fedratinib derived radioactivity was primarily excreted in feces following a single oral dose of radiolabeled fedratinib to healthy subjects.

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin‐6 (IL‐6), soluble IL‐6 receptor, and C‐reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single‐dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target‐mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7‐15 days for CRP and 3‐5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.

Evidence suggests that effects of interleukin-6 pathway inhibitors sarilumab, tocilizumab, and sirukumab on absolute neutrophil count (ANC) are due to margination of circulating neutrophils into rapidly mobilizable noncirculating pools. We developed a population pharmacodynamic model using compartments for neutrophil margination and ANC-specific tolerance to describe rapid, transient ANC changes in blood following administration of subcutaneous sarilumab and intravenous/subcutaneous tocilizumab based on data from 322 patients with rheumatoid arthritis in two single-dose (NCT02097524 and NCT02404558) and one multiple-dose (NCT01768572) trials. The model incorporated a tolerance compartment to account for ANC nadir and beginning of recovery before maximal drug concentration after subcutaneous dosing, and absence of a nadir plateau when the ANC response is saturated after subcutaneous or intravenous dosing. The model effectively describes the ANC changes and supports neutrophil margination and tolerance as an explanation for the absence of increased infection risk associated with low ANC due to interleukin-6 pathway inhibitor treatment.

Background Sarilumab is a human monoclonal antibody blocking the interleukin-6 receptor alpha (IL-6Rɑ) approved for the treatment of moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to other disease-modifying antirheumatic drugs. Objective The aim of the current analysis was to describe sarilumab exposure–response relationships. Methods Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed describing the time course of the 28-joint disease activity score by C-reactive protein (DAS28-CRP) and absolute neutrophil count (ANC) using data from phase I–III studies (NCT01011959, NCT01061736, NCT01709578, NCT01768572) after subcutaneous sarilumab 50–150 mg every week or 100–200 mg every 2 weeks. Results The time course of DAS28-CRP and ANC after sarilumab administration was described by semi-mechanistic, indirect-response models. Drug effect was predicted to be numerically greater at median exposure for the 200 mg every 2 weeks regimen versus the 150 mg every 2 weeks regimen, for both DAS28-CRP (50% vs. 47%) and ANC reduction from baseline (39% vs. 31%), with the latter showing less fluctuations within a dosing interval. Four covariates were retained in the final models: body weight, baseline rheumatoid factor status, anti-cyclic citrullinated peptide status, and concomitant methotrexate. There was no clinically meaningful influence of investigated covariates for either model. Conclusion The PopPK/PD models showed numerically greater reductions in DAS28-CRP and ANC with sarilumab 200 mg every 2 weeks than with 150 mg every 2 weeks. There was no clinically meaningful influence of investigated covariates. These data contribute to the totality of evidence that supports a sarilumab subcutaneous starting dose of 200 mg every 2 weeks, with a subsequent reduction to 150 mg every 2 weeks in the event of laboratory abnormalities such as neutropenia.

Fedratinib is an oral, selective Janus kinase 2 inhibitor that is approved in the United States for the treatment of patients with intermediate-2 or high-risk myelofibrosis. Pharmacokinetics and tolerability of fedratinib in subjects with renal impairment (RI) and hepatic impairment (HI) were evaluated in two separate studies. In the renal study, male and female subjects with stable, chronic mild, moderate, and severe RI, as well as those with end-stage renal disease, were included. The hepatic study included subjects with stable, chronic mild HI. Both were phase 1, multicenter, open-label, single-dose studies, and included matched healthy subjects. Subjects received a single oral dose of fedratinib 300 mg on day 1, were discharged on day 4, returned for clinical visits on days 5–12, and had their end-of-study visit between days 14 and 16. Thirty-six and 17 subjects were included in the renal and hepatic studies, respectively. In the renal study, fedratinib area under the plasma concentration–time curve from time 0 to infinity (AUCinf) was 1.9- and 1.5-fold higher in subjects with severe and moderate RI, respectively, than in matched healthy subjects. In the hepatic study, fedratinib AUCinf did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment–emergent adverse events were gastrointestinal and mild. Mild RI and HI do not necessitate fedratinib dosage adjustments. Subjects with moderate RI should be monitored (with dosage adjustments made as necessary), whereas those with severe RI should receive a daily dose of 200 mg, reduced from the indicated dose of 400 mg.

Objective The purpose of this study is to understand the self-reported advantages and disadvantages of socially networking about body image/eating disorders (EDs) and to examine the openness of these participants to online outreach and support for ED symptoms. Method A cross-sectional online survey was conducted with a sample of N = 598. Eligible participants were ≥15 years old, English-speaking, and U.S. residents who endorsed posting or following thin-ideal/body-image content on social media. Quantitative measures were used to assess online peer support and online interaction preferences, and to identify ED symptoms. Deductive and inductive qualitative approaches were used to analyze open-ended items about the advantages and disadvantages of social networking about thin-ideal content on social media platforms (SMPs). Results Among those who posted about the thin-ideal on social media, 70% felt that the peer responses were positive and supportive. Participants generally favored online interaction, and a third stated that they would accept support from someone they did not know online (38%). The most common advantages noted for posting/following thin-ideal content on SMPs were motivation/encouragement to engage in a certain behavior, socializing, and information giving/seeking. The most common disadvantages mentioned for posting/following thin-ideal content on SMPs were that the content elicits negative/bad feelings, having to deal with the negative consequences/reactions of others when socially networking about this topic, and that it triggers a desire to engage in ED behaviors. Discussion With these findings, researchers, health practitioners, and social media administrators can devise ways to reduce harmful consequences of posting/following body-image/ED content on social media.

Fedratinib is an orally administered Janus kinase 2-selective inhibitor that is indicated for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis in the United States. Fedratinib is metabolized by multiple cytochrome P450s (CYPs) in vitro, with the predominant contribution from CYP3A4. The primary objective of this study was to evaluate the effects of 14-day repeated 200 mg twice daily (BID) oral doses of a strong CYP3A4 inhibitor, ketoconazole, on a sequential ascending single oral dose of fedratinib in healthy male subjects. An open-label, fixed-sequence, two-treatment cross-over study was conducted. Two cohorts of healthy adult males received two single doses of fedratinib (50 mg in Cohort 1 and 300 mg in Cohort 2) with one dose administered alone on Day 1 of Period 1 and the other dose coadministered with ketoconazole in the morning of Day 6 of Period 2. Subjects in both cohorts received 200-mg BID (Days 1–14) ketoconazole during Period 2. Coadministration of repeated 200-mg BID oral doses of ketoconazole for 14 days increased fedratinib exposure by 3.85- and 3.06-fold for area under the plasma concentration–time curve from time zero to infinity following a single oral dose of fedratinib of 50 and 300 mg, respectively. Oral administration of a single dose of 50 or 300 mg of fedratinib, administered alone or coadministered with steady-state ketoconazole, was safe and tolerable in the healthy male subjects. These results serve as the basis for fedratinib dose reduction when fedratinib is coadministered with strong CYP3A4 inhibitors.

Background Individuals with depression may not seek treatment for their symptoms due to several types of barriers to treatment. In support of the growing research on mental health care access and the role of social media, this study aimed to increase knowledge of these barriers among social media users. Methods Participants were recruited from several social media platforms, including Instagram, Facebook, Twitter, Reddit, Tumblr, and online depression forums. Eligible participants had endorsed having posted about feeling sad or depressed on social media, or followed social media groups that post about depression-related topics. Participants completed an online survey about their depression symptoms, interest in treatment, and potential barriers to accessing treatment. Results Of the participants reaching criteria for depression, those with major depression were more likely to seek out treatment, to report an unmet need for treatment, and have a higher risk of suicide. For participants with major depression, barriers to treatment were more likely to be attitudinal, while participants with mild depression experienced more structural barriers. Conclusions This study demonstrates several barriers to treatment that occur for individuals struggling with depression, and that online platforms are effective mediums to recruit individuals with depression symptoms who seek mental health support.

Objectives To assess the safety and pharmacokinetics (PK) of single-dose subcutaneous (SC) sarilumab or tocilizumab SC ± methotrexate (MTX) and to assess the pharmacodynamics (PD) of sarilumab SC or tocilizumab SC monotherapy in Japanese rheumatoid arthritis (RA) patients. Methods TDU13402 was a randomized, double-blind, placebo-controlled, single-ascending dose Phase 1 study (NCT01850680). Twenty-four patients (6 per treatment group) received sarilumab 50, 100, or 200 mg plus MTX or placebo (2 per cohort) on Day (D) 1; PK and safety were assessed through D57. PDY14191 was a randomized, open-label, single-dose study (NCT02404558). Thirty patients (15 per arm) received sarilumab 150 mg or tocilizumab 162 mg on D1; PK, PD, and safety were assessed through D43. Results TDU13402: mean serum sarilumab exposure increased in a greater than dose proportional manner from 50 to 200 mg dose with no clinically meaningful increase in treatment-emergent adverse events (TEAEs). PDY14191: PK profiles of single-dose sarilumab 150 mg or tocilizumab 162 mg were similar; some numerical differences in PD profiles and TEAEs were observed. Neutrophil count decrease/neutropenia was the most frequently reported TEAE with sarilumab treatment in both studies. Conclusions PK, PD, and safety profiles of single-dose sarilumab SC with/without MTX were consistent with results anticipated in Japanese patients with RA.

Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, has demonstrated efficacy and an acceptable safety profile in adult and pediatric patients with moderate-to-severe atopic dermatitis (AD) and other type 2 inflammatory diseases. Dupilumab is available in 200- and 300-mg strengths as a prefilled syringe with a needle shield (PFS-S), and more recently as an autoinjector (AI) device. This study was designed to assess the pharmacokinetic (PK) comparability of a single subcutaneous (SC) dose of dupilumab 200 mg, delivered by 2 different devices, AI (test) versus PFS-S (reference). A total of 130 healthy male and female participants were enrolled in this phase 1 parallel design study, with 128 evaluable for PK. Following dupilumab 200-mg SC injection, dupilumab exposure in serum was similar for both AI and PFS-S. The geometric mean ratios of PK parameters with 90% confidence intervals were 1.08 (0.97-1.21) for maximum serum concentration (C

Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.

Background and Objective Sarilumab binds to the interleukin-6 receptor with high affinity, inhibiting cis and trans signaling by interleukin-6. Sarilumab has demonstrated efficacy and safety in patients with rheumatoid arthritis. The objective of this study was to develop a population-pharmacokinetic model using data from 1770 patients with rheumatoid arthritis across phase I–III studies. Methods Potential covariates were identified using a stepwise forward-addition and backward-deletion strategy, and the final model was evaluated by visual predictive check and bootstrap methods. Results Sarilumab pharmacokinetics is described by a two-compartment model with first-order absorption and parallel linear and nonlinear Michaelis–Menten elimination. A subcutaneous dose of sarilumab 200 mg every 2 weeks resulted in more pronounced saturation of the nonlinear clearance pathway over the dosing interval than 150 mg every 2 weeks. Steady-state exposure (area under the plasma concentration–time curve from day 0 to day 14) increased twofold with dose escalation from 150 to 200 mg every 2 weeks. Body weight, anti-drug antibody status, sarilumab drug product, sex, creatinine clearance, albumin, and baseline C-reactive protein levels were identified as significant covariates according to the predefined statistical significance criteria in stepwise covariate searches. The main intrinsic source of pharmacokinetic variability in exposure was body weight. Compared with a typical 71-kg patient, the area under the plasma concentration–time curve from day 0 to day 14 was 20–23% lower for an 83-kg patient and 20–25% higher for a 62-kg patient. Conclusions These findings, combined with the safety and efficacy data, indicated limited clinical relevance of body-weight effect on sarilumab exposure. No adjustment in sarilumab dose is required for body weight or any other demographics assessed. Electronic supplementary material The online version of this article (10.1007/s40262-019-00765-1) contains supplementary material, which is available to authorized users.

Introduction: Fine-needle aspiration (FNA) is a well-established method for sampling breast lesions with high accuracy and positive predictive value. Despite its decline in recent years relative to the use of core needle biopsies, there are several advantages to FNA which include cost-effectiveness, low complication rate, and the ability to perform rapid on-site evaluation (ROSE). The aim of this study was to evaluate breast FNAs with ROSE to identify diagnostic challenges during ROSE. Materials and Methods: We identified all breast FNAs with ROSE performed at Massachusetts General Hospital from January 2014 to December 2019. From the electronic medical record, clinical, radiological, and follow-up pathology results were recorded. Comparison between the rapid and final cytological diagnosis was made. All discrepancies were documented with major discrepancy defined as a malignant rapid interpretation not confirmed on final diagnosis or a negative rapid interpretation upgraded to suspicious or positive on final diagnosis. Results: The study cohort consisted of 483 breast FNAs with ROSE. The rapid and final cytological interpretations showed good correlation, with only 6 (1.2%) major discrepancies. Problematic areas included low-grade, lobular, and fibroepithelial lesions with low cellularity being a contributory factor to misclassification. Conclusions: FNA remains a highly accurate method for the evaluation of breast lesions with ROSE.

Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double-blind, placebo-controlled, parallel-group, phase III trials in adolescents (12-17 years; LIBERTY AD ADOL) and children (6-11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure-response relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate-to-severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w) (200 mg q2w, baseline weight

Background Many individuals misusing opioids do not enter into treatment. The question of who enters into treatment for their opioid abuse and under what circumstances is complex and shaped by multiple factors. The objective of the current study is to explore the risk factors for wide-ranging and numerous barriers to treatment among social media users. Method Opioid-related forums within a popular social media platform were used to recruit non-treatment engaged individuals (≥15 years) who had misused opioids in the past month ( n = 144; 66% male; median age 28). Four treatment barrier factors were identified utilizing principle component analysis: (1) stigma, (2) awareness, (3) attitudinal, and (4) denial. A structural equation model (SEM) was then created to explore the risk factors for different types of barriers to OUD treatment. Results The most common barriers among participants not engaged in treatment for their opioid misuse were the belief that one should be able to help themselves with their condition (66%), treatment was too expensive (63%), and worries about being labeled or judged (57%). Additionally, SEM results demonstrate stigma barriers, awareness, and attitudinal barriers were associated with mental health comorbidities, opioid abuse and dependence severity, and treatment history. Denial barriers, however, were only associated with treatment history, and structural/financial barriers were only associated with opioid abuse and dependence severity. Conclusions Our research findings are relevant for underscoring the wide-ranging and numerous barriers to treatment faced by individuals misusing opioids that are especially concentrated among those who also struggle with comorbid mental illness.

Objective To evaluate the outcome following the strategy of endoscopic R0 resection (ER) plus adjuvant treatment (AT) versus esophagectomy for esophageal squamous cell cancer in T1a invading muscularis mucosa (M3)-T1b stage. Methods We evaluated the outcomes of 46 esophageal squamous cell cancer (ESCC) patients with T1aM3-T1b stage who underwent ER + AT from the Esophageal Cancer Endoscopic Therapy Consortium (ECETC) and compared these outcomes to 92 patients who underwent esophagectomy. Propensity score matching (1:2) was used, with overall survival (OS) and relapse-free survival (RFS) being compared between the two groups. Results During a median follow-up of 32 months, there were no statistical differences (P = 0.226) in OS between the two groups. The 1-, 2-, and 3-year overall survival in the esophagectomy group was 95%, 91%, and 84%, respectively. There were no mortalities within three years in the ER + AT group. The RFS between the two groups was also not significantly different (P = 0.938). The 1-, 2-, and 3-year RFS of patients in the esophagectomy group was 90%, 90%, and 83%, respectively, while it was 97%, 94%, and 74% in the ER + AT group, respectively. The local recurrence rates between the two groups were not significantly different (P = 0.277). Conclusions This first multicenter analysis showed similar outcomes were found regarding OS and RFS between the two groups in T1aM3-T1b stage patients. ER + AT may be considered in high-risk patients or for those who refuse esophagectomy.

INTRODUCTION: Individuals who feel discomfort about their HIV status could be reluctant to disclose to others their status; ultimately, these sentiments may lead to depression, social isolation and poor adherence to medication. This study seeks to examine the associations between discomfort with HIV status, hopelessness, and depression among adolescents in Uganda. METHODS: We used baseline data from the Suubi+Adherence study, which recruited a total of 702 adolescents (ages 10–16 years) living with HIV in southwestern Uganda. Structural equation models were conducted separately among in-school adolescents and out-of-school adolescents to assess the hypothesized associations between discomfort level with HIV status and depressive symptoms and if this association was mediated by hopelessness. RESULTS: Out-of-school adolescents had significantly higher depression scores compared with those in-school youth (M = 6.24 vs. M = 5.03, p < 0.001). Although high discomfort level with HIV status was significantly associated with higher depression scores among both in-school adolescents and out-of-school adolescent, this association among out-of-school adolescents (B = 0.49, 95%CI: 0.19, 0.79), was more substantial than for in-school adolescents (B = 0.10, 95%CI: 0.03, 0.17). Additionally, hopelessness was found to be a full mediator for this association among in-school adolescents and a partial mediator for out-of-school adolescents. DISCUSSION: One’s discomfort with their HIV status and the extent to which they are hopeful about the future can contribute to the development of depressive symptoms. These factors need to be further considered in the development of assessments and interventions as they may be vital for the treatment of depression among adolescents living with HIV.

Fedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail. An open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15. Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration–time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27–2.47) for metoprolol, 2.82-fold (90% CI 2.26–3.53) for omeprazole, and 3.84-fold (90% CI 2.62–5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4β-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib. Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.

Purpose This study examines the extent to which three mental health measures (hopelessness, depression, and poor self-concept) are improved through a family-based economic intervention implemented among adolescents living with HIV in Uganda. Methods We used repeated measures from Suubi + Adherence, a large-scale 6-year (2012–2018) longitudinal randomized controlled trial. Bivariate analyses were conducted to test for observable group differences between the intervention and control conditions. Multilevel piecewise repeated measure mixed models were then conducted to assess hypothesized time × intervention interaction in changes in hopelessness, depression, and self-concept using participant-specific follow-up intervals. Results At 24-month postintervention initiation, adolescents in the intervention condition reported a statistically significant lower hopelessness score than adolescents in the control condition (4.79 vs. 5.56; p = .018; N = 358). At 36-month follow-up, the intervention condition reported a statistically significant lower score on depression in the depression subgroup (N = 344) than the control condition (4.94 vs. 5.81; p = .029). Conclusions The results indicate that family-based economic interventions such as Suubi + Adherence can effectively improve the mental health of adolescents living with HIV who evidenced mental health challenges at baseline. Given the promising positive effects of these interventions, at least in the short term, future studies should investigate strategies to promote the sustainability of these mental health benefits.

Fedratinib, an oral, selective Janus kinase 2 inhibitor with activity against both wild-type and mutant Janus kinase 2, has pH-dependent solubility, with free solubility at pH 1. Concomitant administration of drugs that reduce gastric acid secretion, such as pantoprazole, may decrease the absorption of fedratinib and affect patient outcomes. The aim of this study was to evaluate the impact of 7-day repeated 40-mg doses of pantoprazole on the pharmacokinetic (PK) properties of a single 500-mg dose of fedratinib in healthy male subjects. In this phase I, single-center, open-label, two-period, two-treatment, fixed-sequence crossover study, healthy male subjects were administered a single dose of fedratinib 500 mg on day 1 in Period 1, followed by pantoprazole 40 mg daily for 7 days (day 1 to day 7) and a single dose of fedratinib 500 mg on day 7 in Period 2. After the discontinuation of nine subjects due to vomiting, the protocol was amended to provide ondansetron as antiemetic prophylaxis to an additional ten enrolled subjects. Twenty-six subjects were included. Repeated doses of pantoprazole 40 mg resulted in clinically insignificant increases in fedratinib exposure. Maximum plasma concentration increased by 1.09-fold and area under the plasma concentration–time curve from time 0 to infinity increased by 1.15-fold. All treatment-emergent adverse events were mild or moderate, except for one instance of neutropenia, which was considered unrelated to study intervention. Coadministration with pantoprazole did not have clinically meaningful effects on fedratinib PK. No new or unexpected safety signals were observed with fedratinib.

A cross-industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering.

Sarilumab is a human monoclonal antibody that blocks the interleukin-6 receptor alpha (IL-6Rα). The phase 3 SARIL-RA-EASY study (EASY) assessed the robustness of an autoinjector (pen) for administering sarilumab when used by adults with active moderate-to-severe rheumatoid arthritis (RA) who are candidates for anti-IL-6R therapy in an unsupervised real-world setting. EASY was a 12-week, multicenter, randomized, open-label, parallel-group usability study of the sarilumab pen and prefilled syringe. Patients were randomized 1:1:1:1 to sarilumab 150 or 200 mg every 2 weeks (q2w) administered via pen or syringe, plus background disease-modifying antirheumatic drugs. Patients reported their ability to remove the pen cap and initiate and complete injections; negative responses were defined as product technical complaints (PTCs). The primary endpoint was the number of validated product technical failures (PTFs; PTC with a validated technical cause). This study was not powered to demonstrate bioequivalence or differences in efficacy among groups. A total of 217 patients were randomized. There were 600 successful injections with the sarilumab pen in 108 patients and no pen-associated PTFs. One PTC was observed (the pen was mistakenly activated before injection). At week 12, 88% of patients indicated the pen was “easy” to use, and 98% reported they were “satisfied” with the pen. Proportions of patients achieving an American College of Rheumatology 20/50/70 response and a 28-joint disease activity score by C-reactive protein

Background Dupilumab, a fully human monoclonal antibody targeting IL-4Rα, has demonstrated rapid and sustained improvements in clinical outcomes in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps. Methods In a phase 1, double-blind, ascending-dose study, 30 healthy Chinese adults were randomized to single subcutaneous doses of dupilumab 200, 300, 600 mg, or placebo. In a phase 3, double-blind study, 165 Chinese adults with AD were randomized to dupilumab 300 mg or placebo every 2 weeks. Results Following single doses of dupilumab 200, 300, and 600 mg in the phase 1 study, mean serum maximum concentrations (Cmax) were 25.4 ± 4.0, 37.2 ± 14.5, and 77.3 ± 19.0 mg/L, respectively. For a 1.5-fold increase in dupilumab dose, 1.31-, 1.73-, and 1.66-fold increases in Cmax, area under the curve to real time (AUClast), and extrapolated to infinity (AUC) were observed, respectively, while a 2-fold dose increase resulted in 2.17-, 2.81-, and 2.80-fold increases, respectively. In the phase 3 study, mean dupilumab trough concentrations were 78.8 ± 32.0 and 86.4 ± 33.6 mg/L at weeks 12 and 16, respectively. Conclusions Cmax increased approximately proportionally to dose, while AUC and AUClast increased greater than proportionally. Dupilumab pharmacokinetics were generally comparable between Chinese and non-Asian healthy subjects (single dose) and between Chinese and non-Asian AD patients (repeated doses), with differences accounted for by body weight. As differences in exposure by weight are unlikely to be clinically relevant based on late-stage study results, no dose adjustment by ethnic origin or weight is required.

Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters.Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details.43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.).Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, Foral and relative AUC (Frel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations.A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.

Background Objectives The in vitro binding affinity of sarilumab (KD 61.9 pM) for the human interleukin-6 receptor (IL-6R) is 15- to 22-fold higher than tocilizumab.1 We explored the relationship between IL-6R RO, relevant pharmacodynamic (PD) variables (eg CRP), and potential clinical relevance of the differences between sarilumab and tocilizumab. Methods Binding to total soluble IL-6R (sIL-6R) in vivo translates into the quasi-steady-state target-mediated drug disposition pharmacokinetics (PK) and indirect-response PD model with inhibition of elimination of sIL–6R and unbound sIL-6R concentration for both sarilumab and tocilizumab.2–5 PK/PD models were used to simulate sIL-6R RO dynamic profiles (% RO over time) for: sarilumab after subcutaneous (SC) doses of 200 and 150 mg once every 2 wks (q2w); tocilizumab after SC doses of 162 mg q2w and once every wk (qw); and tocilizumab after intravenous (IV) doses of 4 and 8 mg/kg once every 4 wks (q4w). In addition, RO profiles were compared with changes in observed CRP levels in patients with RA following administration of sarilumab SC and tocilizumab IV (ASCERTAIN study; NCT01768572). In this study, 60.8% of patients required an increase in tocilizumab dose from 4 to 8 mg/kg IV during the study period, based on clinical response. Results Sarilumab SC 200 mg q2w achieved >90% RO after the first dose, which was maintained over the dosing interval throughout the 24-wk treatment course; at the lower dose of 150 mg q2w, RO was >90% from the second dose onwards. RO for tocilizumab SC, at 162 mg q2w, was >90% immediately after the first dose but dropped below 50% prior to the second dose. Similarly, for tocilizumab IV at 4 mg/kg q4w, the RO was high immediately after the first dose (>99% at Wk 1) but decreased over the dosing interval. At trough steady-state (Wk 24), RO was greater with sarilumab SC 200 mg q2w (98%) and 150 mg q2w (94%) compared with tocilizumab SC 162 mg q2w (84%) and IV 4 mg/kg q4w (60%). The higher doses of tocilizumab SC 162 mg qw and tocilizumab IV 8 mg/kg q4w were able to maintain RO ≥99% at steady state, similar to sarilumab SC 200 mg at steady state. CRP levels in patients with RA were inversely associated with RO at trough; the greatest suppression in CRP was seen in patients who received sarilumab SC (at either dose) or the higher IV tocilizumab dose (Fig). However, proportionally smaller reductions in CRP levels were observed with the lower IV tocilizumab dose (4 mg/kg q4w), consistent with the lower RO of tocilizumab. Conclusion The higher binding affinity of sarilumab to IL-6R compared with tocilizumab translated into higher RO and greater reduction in CRP levels for sarilumab than tocilizumab, confirming the expected association between RO and PD effect. Sarilumab SC 200 mg q2w led to a rapid and sustained suppression of CRP over the 24-wk interval investigated; however, a higher dose (IV) or frequency of administration (SC) of tocilizumab was required to maintain the same degree of RO and CRP suppression. CRP may be a useful tool in clinical practice for patients treated with an IL-6R blocker. References [1] Rafique A, et al. Ann Rheum Dis 2013;72: Abstr 797. [2] Xu C, et al. PAGE Meeting 2017; Abstr 7283. [3] Huizinga T, et al. Ann Rheum Dis 2014;73:1626–34. [4] Gibiansky L, et al. J Pharmacokinet Pharmacodyn 2012;39:5–16. [5] FDA Clinical Pharmacology Review for tocilizumab, 2013. Acknowledgement Study funding and editorial support (Helen Johns, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interests Christine Xu Shareholder of: Sanofi, Employee of: Sanofi, Patrick Nolain Shareholder of: Sanofi, Employee of: Sanofi, Qiang Lu Shareholder of: Sanofi, Employee of: Sanofi, Anne Paccaly Shareholder of: Regeneron, Amgen, Employee of: Regeneron, Sanofi, Amgen, Melitza Iglesias-Rodriguez Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Gregory St John Shareholder of: Regeneron Pharmaceuticals Inc, Employee of: Regeneron Pharmaceuticals Inc, Chad Nivens Shareholder of: Regeneron, Employee of: Regeneron, Rafael Maldonado Grant/research support from: Sanofi, Esteve, Almirall, GSK, Boehringer, Lundbeck, Grunenthal, UPSA, Uphjon, Uriach, Ferrer, Janus, Aelis, Spherium, Pharmaleads, BRAINco, Phytoplant, Rhodes and GW Pharma., Consultant for: Sanofi, Esteve, Almirall, GSK, Boehringer, Lundbeck, Grunenthal, UPSA, Uphjon, Uriach, Ferrer, Janus, Aelis, Spherium, Pharmaleads, BRAINco, Phytoplant, Rhodes and GW Pharma., Tomonori Ishii Grant/research support from: GSK, Janssen, Consultant for: GSK, Janssen, Speakers bureau: Mitsubishi-Tanabe, Janssen, Chugai, Ono, Sanofi, Abbvie, Eisai, Astellas, UCB, Teijin, Daiichi-Sankyo, Pfizer, Takeda, Asahi, and Kasei Pharma, Ernest Choy Grant/research support from: Amgen, Bio-Cancer, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, and Union Chimique Belge, Consultant for: Abbvie, Amgen, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Celgene, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmacuetical, GlaxoSmithKline, Hospita, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, SynAct Pharma, Sanofi-Genzyme, Tonix and Union Chimique Belge, Speakers bureau: Amgen, BMS, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Hospira, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, and Union Chimique Belge, Vanaja Kanamaluru Shareholder of: Sanofi, Employee of: Sanofi

Background Sarilumab blocks IL-6 from binding to membrane and soluble IL-6 receptor-a. Sarilumab is approved for adults with rheumatoid arthritis (RA) and is being investigated in a Phase 2 trial (NCT02776735) in 2–17-year-old patients (pts) with pcJIA, comprising rheumatoid-factor (RF)-positive and RF-negative polyarticular and extended oligoarticular JIA. Objectives Evaluation of pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of 3 subcutaneous (SC) sarilumab doses in pcJIA. Methods A 12-week dose-finding study was performed to identify an appropriate sarilumab dose for use in the pcJIA population. Pts were divided by body weight into 2 groups: A (30–60 kg) and B (10– Results 42 pts enrolled (20/22 in Groups A/B); mean age was 13.0/5.2 years. At baseline, mean pcJIA duration, number of active joints, and JADAS27-CRP were 4.6/1.7 years, 17.2/11.0, and 22.2/19.1, in Groups A/B, respectively. As in adult pts, sarilumab exhibited nonlinear PK with target-mediated drug disposition (TMDD). Following repeated SC administrations, exposure increased in a greater than dose-proportional manner and accumulated 1.9–4.5-fold over 12 weeks. Sarilumab exposure was similar in both weight groups for each dose (Figure), and comparable to corresponding adult doses. Treatment-emergent adverse events (AEs) were reported in 36/42 (85.7%) pts (comparable across dose and weight groups); infections (28/42, 66.7%) were the most frequently reported AE. 12 grade 3/4 neutropenias were identified, mostly in Dose 3 (n=6) and in Group B (n=8). None was associated with infection; all resolved in a few days. Overall, 4 pts discontinued due to neutropenia and 1 due to alanine aminotransferase increase. There were no serious AEs, no cases of GI perforation, and no deaths. By Week 12, as observed while on-treatment: all pts attained JIA ACR30; 50%, 62%, and 100% of pts attained JIA ACR70 with Doses 1, 2, and 3, respectively; JADAS27-CRP mean % changes from baseline in Doses 1, 2, and 3 were -74.6%, -73.1%, and -87.9%, respectively. Conclusion Sarilumab exhibited nonlinear PK with TMDD. Doses tested in pcJIA yielded similar exposure in both weight groups and were comparable to equivalent doses in adults with RA. All dose regimens proved effective for decreasing disease activity. Safety profile was consistent with class effects; higher incidences of neutropenia were observed with Dose 3, and in pts weighing 10– Acknowledgement Study funding and medical writing support (Joseph Hodgson, Adelphi) provided by Sanofi and Regeneron Disclosure of Interests Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Inmaculada Calvo Penades Grant/research support from: AbbVie, BMS, Clementia, MSD, Novartis, Pfizer, Roche, and Sanofi, Consultant for: AbbVie, and Novartis, Speakers bureau: AbbVie, Novartis, Roche, and SOBI, Nadina E. Rubio Perez Speakers bureau: Abbvie, and Roche, Alexey Maschan: None declared, Pierre Quartier Consultant for: AbbVie, Chugai-Roche, lilly, Novartis, Novimmune, Sanofi, and SOBI, Consultant for: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Zbigniew Żuber: None declared, Marina Stanislav Consultant for: R-Pharm, Raul Barria Consultant for: Tecnofarma, Speakers bureau: Pfizer, and Roche, Daniel Clemente Garulo Speakers bureau: Novartis, and Roche, Gabriel Vega Cornejo Grant/research support from: I currently have no conflicts of interest, I am only setting protocols for the pharmaceutical industry with Parexel, Sanofi and Bristol-Myers Squibb., Nancy Liu Shareholder of: Sanofi, Employee of: Sanofi, Christine Xu Shareholder of: Sanofi, Employee of: Sanofi, Angeliki Giannelou Shareholder of: Regeneron, Employee of: Regeneron, Bolanle Akinlade Shareholder of: Regeneron, Employee of: Regeneron, Lydie Baret-Cormel Shareholder of: Sanofi, Employee of: Sanofi

The olfactory tubercle (OT) is located in the ventral-medial region of the brain where it receives primary input from olfactory bulb (OB) projection neurons and processes olfactory behaviors related to motivation, hedonics of smell and sexual encounters. The OT is part of the dopamine reward system that shares characteristics with the striatum. Together with the nucleus accumbens, the OT has been referred to as the "ventral striatum". However, despite its functional importance little is known about the embryonic development of the OT and the phenotypic properties of the OT cells. Here, using thymidine analogs, we establish that mouse OT neurogenesis occurs predominantly between E11-E15 in a lateral-to-medial gradient. Then, using a piggyBac multicolor technique we characterized the migratory route of OT neuroblasts from their embryonic point of origin. Following neurogenesis in the ventral lateral ganglionic eminence (vLGE), neuroblasts destined for the OT followed a dorsal-ventral pathway we named "ventral migratory course" (VMC). Upon reaching the nascent OT, neurons established a prototypical laminar distribution that was determined, in part, by the progenitor cell of origin. A phenotypic analysis of OT neuroblasts using a single-color piggyBac technique, showed that OT shared the molecular specification of striatal neurons. In addition to primary afferent input from the OB, the OT also receives a robust dopaminergic input from ventral tegmentum (Ikemoto, 2007). We used tyrosine hydroxylase (TH) expression as a proxy for dopaminergic innervation and showed that TH onset occurs at E13 and progressively increased until postnatal stages following an 'inside-out' pattern. Postnatally, we established the myelination in the OT occurring between P7 and P14, as shown with CNPase staining, and we characterized the cellular phenotypes populating the OT by immunohistochemistry. Collectively, this work provides the first detailed analysis of the developmental and maturation processes occurring in mouse OT, and demonstrates the striatal nature of the OT as part of the ventral striatum (vST).

Introduction Elevated interleukin (IL)-6 occurs in patients with active rheumatoid arthritis (RA), which has been shown to lead to a decrease in cytochrome P450 (CYP) enzyme activity and alterations in drug concentrations metabolized by CYP. IL-6 signaling blockade by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. This study evaluated the pharmacokinetic profile of simvastatin (a CYP3A4 substrate) before and 1 week after a single dose of sarilumab (a human monoclonal antibody [mAb] blocking the IL-6Rα) in patients with RA, to assess potential interaction. Methods Nineteen patients with active RA received oral simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. The pharmacokinetic parameters of simvastatin and its primary metabolite, β-hydroxy-simvastatin acid, were calculated using noncompartmental analysis. Results Compared with simvastatin alone, single-dose simvastatin administration 7 days after single-dose sarilumab administration in patients with RA resulted in reduced simvastatin and β-hydroxy-simvastatin acid exposure in plasma. Mean effect ratios (90 % confidence interval) for simvastatin peak plasma concentration (C max) and area under the concentration–time curve extrapolated to infinity (AUC∞) were 54.1 % (42.2–69.4 %) and 54.7 % (47.2–63.3 %), respectively. No changes occurred in time to C max or half-life for either simvastatin or β-hydroxy-simvastatin acid after sarilumab administration. Conclusions Sarilumab treatment resulted in a reduction in exposure of simvastatin, consistent with reversal of IL-6-mediated CYP3A4 suppression in patients with active RA, as was reported for tocilizumab with simvastatin and for sirukumab with midazolam. Clinical trial registration number NCT02017639. Electronic supplementary material The online version of this article (doi:10.1007/s40262-016-0462-8) contains supplementary material, which is available to authorized users.