Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps.

AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.

Challenges in Assessing COVID-19 Vaccines Safety Signals-The Case of ChAdOx1 nCoV-19 Vaccine and Corneal Graft Rejection.

The rapid and large-scale roll-out of new COVID-19 vaccines has led to unprecedented challenges in assessing vaccine safety. In 2021, the European Medicines Agency (EMA) processed about 1.7 million safety reports related to COVID-19 vaccines in the EudraVigilance (EV) database and identified more than 900 potential signals. Beyond the large amount of information to be processed, the evaluation of safety signals has faced several difficulties and limitations, both in the assessment of case reports and in the investigation of databases. The evaluation of a signal of corneal graft rejection (CGR) with Vaxzevria® was no exception to this. In this commentary, we present the challenges encountered in making regulatory decisions in the context of evolving evidence and knowledge. The pandemic crisis emphasised the importance of quick and proactive communication to address the many questions and, above all, to ensure the transparency of safety data.

Use and misuse of prescription stimulants by university students: a cross-sectional survey in the french-speaking community of Belgium, 2018.

BACKGROUND: Misuse of prescription stimulants (PS) has been reported among students to enhance academic performance in Flanders (Belgium). However, PS misuse among students in the French-speaking community is unknown. The main purpose of the study was to estimate the prevalence of medical use and misuse of PS by university students in the French-speaking community (Belgium), and to investigate the reasons and sources associated with PS misuse. METHODS: A cross-sectional online survey was performed in 2018. All university students 18 years and older were invited to participate and asked about PS use, including medical (i.e., used for therapeutic purposes) and nonmedical reasons and sources of PS. RESULTS: In total, 12 144 students participated in the survey (median age = 21 years, 65.5% female). The estimated prevalence of PS use was 6.9% (ever use) and 5.5% (past-year). Among ever users, 34.7% were classified as medical users and 65.3% as misusers. Lifetime prevalence of misuse was estimated at 4.5%. The most common reason for medical use was treatment of attention disorder (85.9%). Reasons for misuse were mainly to improve concentration (76.1%) or to stay awake and study longer (50.7%). Friends or acquaintances inside the student community and general practitioners were the main sources of PS for misuse (41.5% and 23.5%, respectively). CONCLUSIONS: This study found that rates of misuse of PS in French-speaking universities in Belgium were in line with studies conducted in Flanders and Europe. Academic institutions can use these results to tailor their drug prevention campaigns.

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization.

BACKGROUND AND OBJECTIVE: In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. METHODS: We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. RESULTS: The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. CONCLUSION: The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.

The need for integrating family planning and postabortion care in China.

OBJECTIVE: To assess the need for integrating postabortion care with family planning services in China. METHOD: We collected data from a clinic-based study of 24 abortion clinics in 3 large cities in China. RESULTS: There was a total of 287 (10.3%) high-risk abortions among the 2780 respondents, 974 (35%) of whom had had repeated abortions and 48.4% had had 2 abortions within 1 year; 63.7% of the current pregnancies resulted from not using contraceptives; 28.8% and 19.8% of these new pregnancies, respectively, were due to the failure of the rhythm or the withdrawal method; only 9.7% of the respondents consistently used condoms; and only 9.1% could identify the correct time of their first ovulation following an abortion. CONCLUSION: Contraceptive neglect and the high rates of repeated and high-risk abortions call for the integration of postabortion care with family planning services in China.

No evidence of coronavirus infection by reverse transcriptase-PCR in bats in Belgium.

No coronavirus was detected by PCR in lung and intestine samples of 100 bats, mostly common pipistrelles (Pipistrellus pipistrellus), collected dead between 2008 and 2013 for rabies surveillance in Belgium. The negative results contrast with the high prevalence of coronaviruses detected in fecal pellets from live-captured bats in some European countries.

Monitoring of all-cause mortality in Belgium (Be-MOMO): a new and automated system for the early detection and quantification of the mortality impact of public health events.

OBJECTIVES: Be-MOMO is the monitoring of all-cause death registry data in Belgium. The new methods are described and the detection and quantification of outbreaks is presented for the period April 2006-March 2007. Sensitivity, specificity and timeliness are illustrated by means of a temporal comparison with known health events. METHODS: Relevant events are identified from important mortality risks: climate, air pollution and influenza. Baselines and thresholds for deaths by gender, age group, day and week are estimated by the method of Farrington et al. (J R Stat Soc Ser A, 159:547-563, 1996). By adding seasonal terms to the basic model, a complete 5-year reference period can be used, while a reduction of noise allows the application to daily counts. RESULTS: Ignoring two false positives, all flags could be classified into five distinct outbreaks, coinciding with four heat periods and an influenza epidemic. Negative deviations from expected mortality in autumn and winter might reflect a displacement of mortality by the heat waves. Still, significant positive excess was found during five influenza weeks. Correcting for the delay in registration of deaths, outbreaks could be detected as soon as 1-2 weeks after the event. CONCLUSION: The sensitivity of Be-MOMO to different health threats suggests its potential usefulness in early warning: mortality thresholds and baselines might serve as rapid tools for detecting and quantifying outbreaks, crucial for public health decision-making and evaluation of measures.

HIV testing and sexually transmitted infection care among sexually active youth in the Balkans.

In light of the imminent threat of a growing HIV epidemic in east and southeast Europe, optimal accessibility of primary and secondary HIV preventative interventions, including HIV testing and sexually transmitted infection (STI) care, are fast becoming public health priorities. We surveyed 2150 high school students in Bosnia and Herzegovina, FYR of Macedonia, Serbia, and Montenegro to examine the uptake of HIV testing and associated predictors. Among sexually active youth (n = 651), 5.9% had already been tested for HIV. In marginal logistic regression, country of origin, type of high school, knowing a friend or relative with HIV, poor self-assessed health status, suspicion of having had an STI, and not having used a condom at first sex were independently associated with HIV testing. Fear of the diagnosis, fear of violation of confidentiality, and not knowing where to go for HIV testing were reported as barriers to HIV testing. Of sexually active adolescents who thought they might have contracted an STI, only 42% had subsequently visited a doctor or health facility. The main reasons for not doing so were spontaneous disappearance of the complaints, fear of the diagnosis and being ashamed of discussing the problem. In conclusion, the uptake of HIV testing among this population of sexually active, urban high school students was found to be low, although a higher prevalence of HIV testing history was observed among students showing evidence of risky sexual behavior. Practical and psychological factors seem to challenge the accessibility of facilities for HIV testing and STI care.