Hydroxychloroquine is an antimalarial drug being tested as a potential treatment for the novel coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2. Although the efficacy of hydroxychloroquine for COVID-19 remains uncertain, it may serve as a potential prophylactic agent especially in those at high risk, such as healthcare workers, household contacts of infected patients, and the immunocompromised. Our aim was to identify possible hydroxychloroquine dosing regimens through simulation in those at high risk of infections by optimizing exposures above the in vitro generated half maximal effective concentration (EC 50 ) and to help guide researchers in dose-selection for COVID-19 prophylactic studies. To maintain weekly troughs above EC 50 in > 50% of subjects at steady-state in a pre-exposure prophylaxis setting, an 800 mg loading dose followed by 400 mg twice or 3 times weekly is required. In an exposure driven, postexposure prophylaxis setting, 800 mg loading dose followed in 6 hours by 600 mg, then 600 mg daily for 4 more days achieved daily troughs above EC 50 in > 50% subjects. These doses are higher than recommended for malaria chemoprophylaxis, and clinical trials are needed to establish safety and efficacy.

Background : Prophylactic voriconazole use is recommended in children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential due to its narrow therapeutic index. Known covariates do not sufficiently explain large interindividual pharmacokinetic (PK) variability of voriconazole. Moreover, knowledge of voriconazole PK for age <2 years is limited. Objectives : We investigated genetic and clinical covariate association with voriconazole interindividual PK variability and subsequently simulated dosing regimens in children. Methods : This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing HCT. We conducted a population PK analysis and tested covariate effects on voriconazole PK, including 67 genetic variants and clinical variables. Results : We analyzed plasma voriconazole and n-oxide metabolite concentrations from 58 children aged <21 years (n=12 in age <2 years). A two-compartment parent mixed linear/nonlinear model best described our data. CYP2C19 phenotype and body weight were significant covariates (both p<0.05). Our model performance in age <2 years was comparable to other age groups. Simulation of the final model suggested the following dosages to attain target steady-state trough concentrations of 1.5 - 5.0 mg/L in CYP2C19 normal phenotype: 16 mg/kg (weight <15 kg), 12 mg/kg (weight 15-30 kg), 10 mg/kg (weight >30 kg), whereas dosages were 33-50% lower for CYP2C19 poor/intermediate and 25-50% higher for CYP2C19 rapid/ultrarapid phenotypes. Conclusions : We propose a new starting dosage regimen, combined with therapeutic drug monitoring for intravenous voriconazole in children of all ages. Future studies should validate this dosing regimen.

Objectives: The current study aimed to evaluate the prevalence, level of knowledge and attitudes to seasonal influenza vaccination among older adults in Jordan. Methods: This was a cross-sectional study in which a close-ended questionnaire was administered to older adults (65 years or older) in two major cities in Jordan between May 2018 and July 2018. A p-value of less than 0.05 was considered the cutoff level for statistical significance. Results: Among 500 participants, only 1.2% (n = 6) received a seasonal influenza vaccine during the previous year. In assessing influenza disease and influenza vaccine knowledge, 47.8% had good knowledge. Around 61% of older adults reported influenza vaccine is effective against preventing influenza however, 49.8% reported that influenza could be treated with the influenza vaccine. Moreover, 27% thought the influenza vaccine is important for older adults. In terms of attitudes toward the vaccine, 24.6% had positive attitudes and 40.6% strongly agreed/agreed that influenza is a serious disease in older adults and they should take the influenza vaccine to prevent influenza. Conclusion:The results of this study showed an extremely poor influenza vaccination rate among older adults and a low level of influenza vaccination knowledge and attitudes.

Aims The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17‐hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH). Methods A nonlinear mixed‐effect modelling approach was used to analyse cortisol, 17‐hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an Imax model. Results Cortisol was characterized by a one‐compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC50 values of cortisol concentrations for cortisol, 17‐hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 μg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC50 values were higher in salt‐wasting subjects than simple virilizers. Production rates of cortisol, 17‐hydroxyprogesterone and androstenedione were higher in simple‐virilizer subjects. Half‐lives of cortisol, 17‐hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively. Conclusion Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17‐hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC‐above‐threshold, time‐within‐range, etc. Our long‐range goal is to uncover dose–exposure–outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.

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