Dose Formulation, Biodistribution and PET Imaging Studies of a First-In-Class Fluorine-18 Organophosphorus Cholinesterase Inhibitor Tracer in Rat

Background:: To investigate dynamic live tissue organophosphorus nerve agent uptake and distribution fates resulting in acetylcholinesterase inhibition, we recently reported the first-in-class fluorine-18 (18F) radiolabeled positron emission tomography (PET) imaging tracer known as [18F]O-(2-fluoroethyl)-O-(p-nitrophenyl)methylphosphonate. This tracer has been initially studied in live rats with PET imaging. Objective.: We sought to evaluate the PET tracer in vivo using a new dose formulation of saline, ethanol and L-ascorbic acid, and compare the influence of this formulation on in vivo tracer performance to previous data collected using a CH3CN:PBS formulation. Methods:: A high molar activity [18F] tracer radiosynthesis was used. Doses were formulated as saline, ethanol (≤ 1%) and L-ascorbic acid (0.1%), pH 4.0-4.5. Stability was evaluated to 6 h. Dose injection (i.v.) into male rats was followed by either ex vivo biodistribution profiling at 5, 30, 90 min, or dynamic 90 min PET imaging. Rat biodistribution and PET imaging data were compared. Results and Discussion:: An optimized radiosynthesis (8 ± 2 % RCY) resulted in stable doses for 6 h (>99%). Arterial blood included tracer and a single metabolite. The ex vivo biodistribution and live tissue PET imaging data revealed rapid radioactivity uptake and distributed tissue levels: heart and lung, highest; liver, moderate; and brain, lowest. Conclusions:: Imaging and biodistribution data were highly correlated with expected radioactivity tissue uptake and distribution in target organs. Lower brain radioactivity levels by PET imaging were found for the new formulation (saline, 1% L-ascorbic acid, < 1% ethanol) as compared to the established CH3CN:PBS formulation. Overall, we find that the i.v. dose formulation changed the in vivo profile of an organophosphorus PET tracer is considered an important finding for future organophosporus PET tracer studies.

2767. Variation in Incidence of Pediatric Herpes Zoster by First- and Second-Dose Varicella Vaccine Formulations

Background Varicella (VAR) and measles-mumps-rubella (MMR) vaccines are recommended for children at ages 12–15 months and 4–6 years. These are administered as separate MMR and VAR vaccines (MMR+VAR) or as combined measles-mumps-rubella-varicella (MMRV) vaccine. Herpes zoster (HZ), caused by wild-type or vaccine-strain varicella-zoster virus, can occur in children after varicella vaccination. It is unknown whether HZ incidence after varicella vaccination varies by vaccine formulation or simultaneous receipt of MMR. Methods Using data from six integrated health systems, we examined HZ incidence among children who turned 12 months old during 2003–2008 and received varicella and MMR vaccines according to routine recommendations. All HZ cases ≥ 21 days after first varicella vaccination were identified using ICD-9 codes from inpatient, outpatient, emergency room encounters, and claims data, through 2014. HZ incidence was examined by vaccine formulation (MMR+VAR, MMRV, or VAR without same-day MMR) and doses received and compared using incidence rate ratios (IRR). Results Among 199,797 children, we identified 601 HZ cases. Crude HZ incidence after first-dose MMR+VAR (18.6 [95% CI 11.1–29.2] cases/100,000 person-years) was similar to the rate after first-dose MMRV (17.9 [95% CI 10.6–28.3] cases/100,000 person-years), but approximately double the rate among those with first-dose VAR without same-day MMR (7.5 [95% CI 3.1–15.0] cases/100,000 person-years); see Table 1. The IRR for HZ after first-dose MMR+VAR or MMRV, compared with VAR, was 2.5 (95% CI 1.4–4.4; P = 0.002). When examining any first or second dose formulation, crude HZ incidence was lower after the second varicella vaccine dose (13.9 cases/100,000 person-years), than in the period before the second dose (i.e., between first and second doses or after the first dose in children with only one dose; 21.8 cases/100,000 person-years, P < 0.0001). HZ incidence was also lower after two varicella vaccine doses in each of the three first-dose formulation groups. Conclusion HZ incidence among children varied by first-dose varicella vaccine formulation and number of varicella vaccine doses. Regardless of the first-dose varicella vaccine formulation, children who received two vaccine doses had lower HZ incidence after the second dose. Disclosures All authors: No reported disclosures.

Dose and formulation of azithromycin in mass drug administration studies: a systematic review protocol

IntroductionAzithromycin has been given for tropical infectious diseases such as trachoma and yaws by mass drug administration (MDA). As well as controlling the infectious disease in question, MDA may have a beneficial effect in reducing mortality in young children. However, the dose, formulation, frequency and duration of azithromycin used in certain infectious diseases may vary in different studies, and these differences may have impacts on the effectiveness of azithromycin MDA. Furthermore, whether the dose, formulation, frequency and duration are associated with the effectiveness of azithromycin for reducing child mortality—if indeed this effect can be confirmed—remain unknown. In this study, we will investigate whether different strategies such as different dose, formulation, frequency and duration affect the effectiveness of azithromycin MDA on the prevalence of certain infectious diseases or child mortality.Methods and analysisA narrative systematic review will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be searched. No language restrictions will be applied. All randomised/quasi-controlled trials, observational studies (cross-sectional studies, cohort studies and case–control studies), case series and registered protocols will be considered. Dose, duration, frequency, rounds and formulations of azithromycin used in MDA will be collected and reviewed. The outcomes will be disease prevalence/control in children and child mortality. Data from the individual studies will not be pooled.Ethics and disseminationFormal ethical approval is not required since data will be collected from published studies. This systematic review will be published in a peer-reviewed journal and presented at conference meetings.PROSPERO registration numberCRD42018114902