The Role of CoLab and GAITS in Enabling the RADx Tech Program.

The RADxSM Tech initiative required a massive mobilization of the biomedical community. It was chartered with the extremely ambitious goal of rapidly developing and deploying innovative tests to detect people infected with the SARS-CoV-2 virus. It needed to do so at a scale and with urgency to get the country back to daily activities such as school and work as soon as possible. It required forming and supporting a diversity of teams with members from around the country and beyond. These teams collaborated in complex workflows that needed to be carefully monitored and tracked. This paper describes the key elements of the secure, web-based infrastructure that was configured to enable the efficient and effective operation of RADx Tech's key processes and address its unique and urgent challenges. One such challenge was to manage the flow of applications through a multi-stage, interactive selection process (using the CoLab platform) and another was to support and facilitate the progress of projects selected for support and funding through an accelerated commercialization program (using the GAITS platform).

Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer-Results from Phase Ib Trial IMU.ACS.001.

PURPOSE: HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988). PATIENTS AND METHODS: A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 µg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1. RESULTS: IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses. CONCLUSIONS: IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 µg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.

Effect of Food Intake and Body Position on the Pharmacokinetics of Swallowed APT-1011, a Fluticasone Orally Disintegrating Tablet, in Healthy Adult Volunteers.

Eosinophilic esophagitis is a common atopic disease of the esophagus. APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate under development for the treatment of eosinophilic esophagitis. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of APT-1011 under fed or fasted conditions in the morning (am) or at bedtime (hs) in the supine position. The study was a randomized, single-dose, 3-way, crossover design in healthy adult volunteers. In each study period participants received 2 3-mg orally disintegrating APT-1011 tablets. Serial plasma samples were collected before dosing and up to 72 hours after each dose. Twenty-two participants completed the study. The fluticasone propionate peak concentration (Cmax ) ranged from 5.97 to 200 pg/mL. Compared with am-fasted dosing, am-fed dosing was associated with a modestly higher Cmax (∼21%) but lower net exposure (area under the concentration-time curve ∼56% difference) and shorter time to reach Cmax (Tmax ) (Tmax fasted = 10 hours, fed = 5 hours). Dosing at hs resulted in an 18% and 32% decrease in Cmax relative to am-fasted and am-fed conditions, respectively. Dosing at hs led to an exposure that was higher than am-fed but lower than am-fasted dosing. Tmax with hs dosing (14 hours) was later than that with am dosing (Tmax fasted = 10 hours, fed = 5 hours). Adverse events were mild. There is low systemic exposure of fluticasone propionate with APT-1011. The rate of absorption was increased with a high-fat meal but decreased with hs dosing, suggesting the potential for longer dwell times in the esophagus.

WITHDRAWN: (440) Opioid-Induced Nausea and Vomiting (OINV) in Post-Operative Patients: A Comparison of CL-108 to Hydrocodone 7.5 mg/Acetaminophen 325 mg.

The Publisher regrets that this abstract is an accidental duplication of abstract (436), also published in the 2016 American Pain Society Scientific Meeting abstracts supplement: J Pain 17:S83, 2016, http://dx.doi.org/10.1016/j.jpain.2016.01.413. The duplicate abstract (440) has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: (438) Efficacy of CL-108 compared to hydrocodone 7.5 mg/acetaminophen 325 mg in preventing vomiting and the use of anti-emetics, Opioid-Induced Nausea and Vomiting (OINV).

The Publisher regrets that this abstract is an accidental duplication of abstract (431), also published in the 2016 American Pain Society Scientific Meeting abstracts supplement: J Pain 17:S82, 2016, http://dx.doi.org/10.1016/j.jpain.2016.01.408. The duplicate abstract (438) has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Quantification of human serum insulin concentrations in clinical pharmacokinetic or bioequivalence studies: what defines the "best method"?

BACKGROUND: Historically, quantitative clinical diagnostic assays (QCDAs) have not been accepted for use in pharmacokinetic or bioequivalence studies because they do not fully comply with the US Food and Drug Administration (FDA) Guidance for Industry: Bioanalytical Method Validation (e.g., full calibration curve not generated with each analytical run). Samples from a bioequivalence study were analysed for insulin and C-peptide concentrations with QCDAs and guidance-conforming radioimmunoassays (RIAs) and the results compared across and within assays. METHODS: Serum samples (n=1913) from study MKC-TI-142 were analysed first using the Roche E170 electrochemiluminescence immunoassay (ECLIA) for insulin concentration and the Immulite 2000 chemiluminescence immunoassay (CLIA) for C-peptide, and then using the corresponding Millipore RIAs. RESULTS: The insulin assays were highly correlated: r2=0.92 excluding samples requiring dilution and R2=0.88 including all samples. There was increasing negative bias of the ECLIA compared with the RIA with increasing insulin, especially with samples that required dilution for the RIA. The ECLIA had significantly fewer below-quantifiable-limit samples, a larger dynamic analysis range without dilution, and tighter agreement within incurred sample reanalysis (ISR) as compared with the RIA. The C-peptide assays showed good agreement but the CLIA method produced ISR results that were in closer agreement with the original values. CONCLUSIONS: The science indicates that the QCDAs are appropriate for the quantification of serum insulin (ECLIA) and C-peptide (CLIA) concentrations in human pharmacokinetic and bioequivalence studies even though the calibration curve is not generated in each analytical run.

Insulin lung deposition and clearance following Technosphere® insulin inhalation powder administration.

PURPOSE: To determine distribution and deposition of Technosphere® Insulin (TI) inhalation powder and the rate of clearance of fumaryl diketopiperazine (FDKP; major component of Technosphere particles) and insulin from the lungs. METHODS: Deposition and distribution of (99m)pertechnetate adsorbed onto TI immediately after administration using the MedTone® inhaler was quantified by gamma-scintigraphy. Clearance from the lungs was studied in a second experiment by serial bronchoalveolar lavage (BAL) after administration of TI inhalation powder and assay of the recovered fluid for FDKP and insulin. RESULTS: Following inhalation, ~60% of radioactivity (adsorbed on TI) emitted from the inhaler was delivered to the lungs; the remainder of the emitted dose was swallowed. Clearance from the lung epithelial lining fluid (ELF) of FDKP and insulin have a half-life of ~1 hour. CONCLUSION: TI inhalation powder administered via the MedTone inhaler was uniformly distributed throughout the lungs; ~40% of the initial cartridge load reached the lungs. Insulin and FDKP are quickly cleared from the lungs, mainly by absorption into the systemic circulation. The terminal clearance half-life from the lung ELF, estimated from sequential BAL fluid measurements for both components, was ~1 hour. Since there is an overnight washout period, the potential for accumulation on chronic administration is minimal.

Linking urban families to community resources in the context of pediatric primary care.

INTRODUCTION: Pediatric guidelines emphasize the importance for healthcare providers to view children in the context of family and community, and promote community resources at visits. In 2006, a Family Help Desk (FHD) was established in an urban academic-based clinic in Baltimore, MD to assist healthcare providers in educating families about available community-based resources. METHODS: A longitudinal cohort pilot study was conducted during a 6-week period in 2007 to evaluate the impact of the FHD in connecting at-risk families to community resources. RESULTS: Overall, 6% of parents (n=59) who brought their child for a scheduled clinic visit accessed the FHD. Parents had a mean of 1.7 social needs, including after-school programs and childcare (29%), employment (13%), housing (12%), and food (11%). Most parents who utilized the FHD (64%) contacted a community resource or service within 6 months of their clinic visit. Nineteen parents (32%) who utilized the FHD enrolled in community programs. CONCLUSION: A clinic-based multi-disciplinary model can empower families to connect with community-based resources for basic social needs. PRACTICE IMPLICATIONS: The Family Help Desk model has great potential for addressing family psychosocial needs, and educating families about community resources within the context of pediatric primary care.

Pharmacokinetics of E5564, a lipopolysaccharide antagonist, in patients with impaired hepatic function.

E5564 is a structural analog of the Lipid A portion of lipopolysaccharide (LPS). E5564 has been tested in several in vitro and in vivo models and has demonstrated its effectiveness against LPS. It is intended to be an antagonist of LPS to reduce the morbidity and mortality associated with sepsis syndrome. This study assessed the pharmacokinetics (PK) of E5564 in patients with impaired hepatic function. E5564 was administered via intermittent intravenous infusion every 12 hours for six times to 24 hepatic-impaired patients (12 each to Child-Pugh Classifications A and B) and 24 matching healthy volunteers. Plasma samples were analyzed by LC/MS/MS. A one-compartment model resulted in good and comparable fits for all volunteers. Regardless of liver disease state, none of the PK parameters compared (i.e., Cmax (0-12),tmax (0-12),CL,t1/2, Vss, AUC(0-12), AUC(0-last), AUC(0-infinity), C(ss,min), C(ss,max), and C(ss,av)) exhibited any difference between these two groups. This suggested that the exposure of E5564 in volunteers was independent of hepatic function. Thus, no dose adjustment is needed in patients with hepatic impairment classified as Child-Pugh A and B.

Meeting the challenge of bioterrorism: lessons learned from West Nile virus and anthrax.

Hospital emergency departments (EDs) and ambulatory clinics may be the first to recognize illness related to a bioterrorist event. Every health-care institution must develop a weapons-of-mass- destruction (WMD) preparedness plan as part of its all-hazards disaster planning. As part of an all-hazards disaster plan, WMD preparedness should use the incident-command model to insure the required chain of command for effectively coordinating activities between hospital departments and external agencies. Preparedness for bioterrorism poses unique challenges. In the event of a biological attack, the hospital infection control staff and administration must already have in place the means to communicate with local and state public health agencies, the Centers for Disease Control and Prevention (CDC), local law-enforcement agencies, and the Federal Bureau of Investigation (FBI). Local and regional planners must consider how to coordinate the responses of emergency medical services (EMS), police, and fire departments with healthcare providers and the news media. Most hospitals are ill equipped to deal with a catastrophic event caused by WMD. The burden of responding to such events will fall initially on ED physicians and staff members. The severity of such an incident might be mitigated with careful planning, training and education. The responses of one hospital network to the outbreak of West Nile virus and, more recently, to the threat of anthrax, are presented as guides for bioterrorism preparedness.

Grapefruit juice reduces the oral bioavailability of fexofenadine but not desloratadine.

BACKGROUND: Certain foods, such as grapefruit juice, are known to substantially alter the bioavailability of some drugs. These effects may be mediated by interactions with enzyme systems, such as cytochrome P450, or with active transporter systems, such as P-glycoprotein and organic anion transporting polypeptides. OBJECTIVE: To assess the effect of consumption of grapefruit juice on the oral bioavailability of two nonsedating antihistamines, fexofenadine and desloratadine. DESIGN: Non-blinded, randomised, single-dose, four-way crossover study. PARTICIPANTS: Twenty-four healthy adult volunteers. INTERVENTIONS: Single oral doses of desloratadine 5mg and fexofenadine 60mg taken without and with grapefruit juice (pretreatment with 240ml of double-strength juice three times daily for 2 days prior to administration of study drug, plus the same amount simultaneously with, and 2 hours after, the drug dose). Each treatment was separated by at least 10 days. MAIN OUTCOME MEASURES: Log-transformed pharmacokinetic parameters [peak plasma concentration (C(max)) and area under the curve (AUC)], time to maximum concentration, elimination half-life and electrocardiographic (ECG) parameters. RESULTS: Comparing the ratio of the pharmacokinetic parameter means (C(max) and AUC) with and without grapefruit juice (expressed as a percentage), the rate (C(max)) and extent (AUC) of absorption of fexofenadine were reduced by 30% by consumption of grapefruit juice. In contrast, the bioavailability of desloratadine was unaffected by grapefruit juice. No clinically significant changes in ECG parameters were observed following coadministration of grapefruit juice with desloratadine or fexofenadine compared with either antihistamine given alone. CONCLUSION: The bioavailability of drugs that do not undergo significant intestinal or hepatic metabolism, such as fexofenadine, may be altered when administered with agents that influence drug transport mechanisms.