Global Collaboration to Provide Drug Interaction Guidance for Nirmatrelvir/Ritonavir

Background: Nirmatrelvir/ritonavir (NMV/r), a preferred antiviral for high-risk outpatients with COVID-19, is associated with major drug-drug interactions (DDIs). Given the lack of DDI data with short course ritonavir (RTV), initial NMV/r product information was extrapolated from chronic, full dose RTV use. In Jan 2022, DDI experts from the University of Liverpool (UoL), NIH COVID-19 Guidelines Panel, and Ontario Science Table (OST) contributors established a global collaboration to address DDI challenges limiting NMV/r use in real-life settings. We report how safe, pragmatic, and consistent resources were developed to support NMV/r prescribing, and the utilization of these resources globally. Method(s): The 3 teams met monthly to discuss DDIs, review NMV/r DDI literature, and achieve consensus on recommendations. Additional experts were invited as needed. Metrics from the UoL DDI checker guided review of most searched DDIs overall and by severity. 2022 usage metrics for each DDI guide were collected. Differences in recommendations between initial DDI guides and product information were compared. Result(s): In 2022, 12 meetings were convened. Each team's DDI guide was revised and expanded (Table 1). To factor in the lower RTV dose and shorter treatment duration, some recommendations differed from product information. Drug categories that required the most discussion and revision included: anticoagulants (ACs), immunosuppressants, calcium channel blockers. NMV/r accounted for 85% of queries on the UoL site. NMV/r DDI guidance was the most viewed page of the NIH guidelines and among the OST ID/clinical care Science Briefs. Top searched drugs on the UoL site with serious DDIs were certain ACs and statins. Utilization of DDI guides was not limited to in-country resources: 51% and 7% of UoL queries came from the USA and Canada, respectively. NIH users followed links to the UoL and OST sites 161,478 and 37,619 times, respectively. Conclusion(s): Significant efforts have been made by the 3 teams to provide upto-date, complementary DDI guidance. Usage metrics confirm the demand for DDI guidance during the pandemic. Cross-utilization of the DDI guides confirms the need for consistency. DDI recommendations were more permissive than initial product information, expanding clinicians' ability to prescribe NMV/r. DDI guidance for ACs and immunosuppressants was particularly challenging. During drug development, complex interactions likely to be encountered in target populations should be addressed.

Differences in Physical and Mental Health of Older Adults over the Covid-19 Pandemic from Face-to-Face versus Hybrid Methods

Background/Purpose: As a result of the COVID-19 pandemic, changes in data collection methods have been introduced in research to ensure continuity despite physical distancing and lockdown restrictions. Our objective was to compare differences in physical and mental health of older adults participating in falls research using data collection methods pre-covid-19 pandemic (face-to-face) and during the pandemic (hybrid). Method(s): Individuals aged 60 years and over with at least one fall in the past 12 months, and controls with no history of falls in the past 12 months were recruited. Pre-pandemic, individuals were interviewed face-to-face exclusively, those interviews after the start of the pandemic were conducted virtually with physical assessments conducted face-to-face to minimize physical contact. Cognitive status, physical performance, psychological status, quality of life, physical activity, and social participation were measured. Result(s): Of the 145 participants of similar socio-demographic backgrounds, 69 were interviewed face-to-face, while 76 were assessed using a hybrid method. Differences were observed in presence of fall characteristics, with fewer fallers seeing a doctor and more fallers attending the emergency department after the start of the pandemic. After adjustment for baseline differences, participants interviewed using hybrid status had lower depression scores (OR (95%CI)=0.29(0.14-0.61)) and stress scores (OR(95%CI)=0.33(0.15-0.72)), but greater fear of falling (OR(95%CI)=2.16(1.04-4.48)) and reduced social participation (OR(95%CI)=2.64(1.20-5.79)). Conclusion(s): Alterations in data collection methods to overcome pandemic restrictions should take into consideration potential differences in individuals who agree to participate as well as the influence of major life events on the psychological status of participants. Copyright © 2022, Full Universe Integrated Marketing Limited. All rights reserved.

SALIVA, NASAL & TEAR PK of EIDD-1931 in PATIENTS with COVID-19 RECEIVING MOLNUPIRAVIR

Background: Molnupiravir, a prodrug of the broadly active, direct-acting antiviral, ribonucleoside analogue EIDD-1931, is a promising COVID-19 drug. Given the primary route of SARS-CoV-2 transmission through respiratory droplets we evaluated EIDD-1931 PK in saliva, nasal secretions and tears of patients with mild-to-moderate COVID-19 through the phase Ib/IIa AGILE platform (NCT04746183). Methods: Patients with PCR-confirmed SARS-CoV-2 infection, within 5 days of symptom onset with mild-to-moderate disease were randomised to oral molnupiravir 300, 600 or 800 mg twice daily. Plasma and non-plasma (saliva, nasal and tear swabs) samples were collected pre-dose, 0.5, 1, 2, and 4 hours post-dose on study days 1 and 5 and molnupiravir and EIDD-1931 measured by LC/MS (lower limit of quantification, 2.5 ng/mL). PK parameters were determined (Phoenix 64, WinNonlin, v. 8.3) and non-plasma:plasma (NP:P) ratios (based on AUC0-4) calculated. Relationships between paired non-plasma and plasma samples were evaluated by linear regression. Results: Twelve participants (n=4 per dose;75% female) completed the study contributing 111, 112 and 97 saliva, nasal and tear samples, respectively. Molnupiravir was detected in 11% of saliva samples [median (range) 4.86 ng/mL (2.63-31.44)] and not evaluated in swabs. Quantifiable EIDD-1931, following molnupiravir 300, 600 and 800 mg twice daily were i) saliva: 17.7 (2.8-133), 16.6 (2.9-469), 25.8 (4.0-230) ng/mL, ii) nasal swabs: 182 (18-1700), 136 (18-917), 295 (24-1879) ng/mL and iii) tears: 297 (24-1650), 176 (16-1260), 307 (32-2760) ng/mL. PK parameters are shown (Table 1). Median (range, CV%) pooled NP:P ratio for saliva was 0.03 (0.01-0.11, 60%;n=16). Nasal and tear ratios were 6-fold higher with values of 0.21 (0.05-0.73, 70%;n=17) and 0.22 (0.09-1.05, 92%;n=12), respectively. Non-plasma and plasma concentrations were significantly correlated (r2: 0.360-0.677;p<0.0001). Of measured saliva, nasal and tear samples, 6, 50 and 61%, respectively were within or above the EIDD-1931 EC90 against SARS-CoV-2 in primary human airway epithelia cultures (approximately 0.5-1 μ M ≈ 130-260 ng/mL). Conclusion: This is the first report of EIDD-1931 PK at sites of initial SARS-CoV-2 exposure in patients with COVID-19. Investigations of PK/PD relationships are warranted;however, these data suggest therapeutic concentrations are potentially achieved in nasal and tear compartments, but not saliva and have important implications for prophylactic coverage.

Qualitative and Digital Research in Times of Crisis: Methods, Reflexivity, and Ethics

Crises such as the COVID-19 pandemic, disasters, or violent conflict present numerous challenges for researchers. Faced with disruption, obstacles, and even danger to their own lives, researchers in times of crisis must adapt or redesign existing research methods in order to continue their work effectively. Including contributions on qualitative and digital research from Europe, Asia, Africa, Australasia, and the Americas, this volume explores the creative and thoughtful ways in which researchers have adapted methods and rethought relationships in response to challenges arising from crises. Their collective reflections, strategies, and practices highlight the importance of responsive, ethical, and creative research design and the need to develop methods for fostering mutual, reflexive, and healthy relationships in times of crisis. © the editors;individual chapters © their respective authors, 2022.

Pattern of Oral and Maxillofacial New Referrals COVID-19 Lockdown

The study aimed to quantify the impact of lockdown during the COVID-19 pandemic on new case referrals to the Oral and Maxillofacial Surgery (OMS) service. The researchers retrospectively reviewed all new referrals received during a government-imposed 47-day lockdown period and a similar period pre-lockdown as a control group. The main outcome was the differences in the number of new case referrals between the two periods. The contributing clinical and demographic factors were also explored. Appropriate bivariate statistics were computed and the level of significance was set at 0.05 for all tests. A total of 309 referrals were received during the study period. There was a reduction of new referrals due to the lockdown from five to two cases per day. There was a statistically significant reduction of cases referred from outpatient and emergency departments. There was also a statistically significant difference with regard to home address distance to the centre. Medically compromised and orofacial infection referrals were not affected by lockdown. The lockdown imposed due to the pandemic has significantly impacted the pattern of new OMS referrals. Referrals for orofacial infections, the medically compromised and inpatients were minimally affected by lockdown.

PBPK modeling of dexamethasone in patients with COVID-19 and liver dysfunction

Background: Patients with pre-existing multimorbidity and liver dysfunction (LD) are more likely to develop severe COVID-19 and have a higher risk of mortality. In severe COVID-19 patients who are mechanically ventilated or require supplemental oxygen, the administration of dexamethasone (DEX) may be life-saving, however the impact of LD on the pharmacokinetics (PK) of DEX is unknown. The aim of the study was to apply PBPK modelling to predict the effect of LD on the PK of DEX in the treatment of COVID-19. Methods: A whole-body PBPK model was designed in Simbiology v. 9.6.0 (MATLAB R2019a) and used to simulate 100 adult individuals. First the model was qualified against reported clinical data for oral (PO) and intravenous (IV) DEX in healthy adults. Physiological changes and portal vein shunt were incorporated into the model to provide a mathematical description of LD that was classified by Child-Pugh (CP) scores A, B and C. The LD model was qualified against IV and PO reported clinical data for both propranolol (healthy adults and CP-A,-B and-C patients) and midazolam (healthy adult and cirrhosis patients). The model was assumed to be verified if the simulated values were within 2-fold of the reported clinical values and if the absolute average-fold error (AAFE) was below 2. The qualified model was then used to simulate the administration of DEX 6 mg (COVID-19 protocol) in patients with LD (CP-A,-B and-C) with and without shunting. The mean shunt index (%) considered in the model was 40 ± 18. Results: The PBPK model was successfully qualified across DEX, midazolam and propranolol with an AUC0-24 average fold of 1.1 and 0.95;AAFE value of 1.1 and 1.2 for healthy and LD individuals, respectively. When compared to healthy adults, the simulated systemic clearance of DEX decreased and the plasma concentrations increased in all patients with LD, as shown in Table 1. Moreover, a significant difference was observed between the AUC0-24 of DEX PO when comparing no shunting and shunting in patients with CP-B and-C. Conclusion: The increased exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Although DEX exposure was predicted to be more than 2 times higher in CP-C individuals, no dose adjustments seem necessary in patients with LD considering DEX's low hepatic extraction, the low dose administered in the COVID-19 protocol and the therapeutic index of DEX.

In Medias Res: Decolonial Interventions Editorial Introduction

Since we announced the call for this Special Issue on Decolonial Interventions: in the middle of decoloniality in mid-2019, it feels like a lot has changed and the “middle” is more entangled and complicated than ever. The COVID-19 pandemic has locked us down to shelter in our places, yet it has made us busier and more connected, and more worried and questioning. The concerns and motivations that stood behind our decision to call for this Special Issue have not been eclipsed, as we might have initially thought. Indeed, our concerns have been magnified and thrust forward as the global spread of the pandemic has been accompanied by the eruption of Black Lives Matter protests against police violence in the US, scenes of pandemic refugees dying on their exodus from locked-down cities in India, toppling statues in Britain and horrendously unjust disparities of sickness and death burdening Black people, Indigenous people and people of colour in different countries. Deep questions about structural injustice and the colonial-modern have (re)surfaced as the entangled roots of oppression and violence have been thrust into the open, making them impossible to ignore. Racism, gender violence, indigenous dispossession and genocide, climate and environmental injustice, forest fires and species extinction render basic human demands for healthcare, shelter, food, clean water and even the universal right to breathe (Mbembe 2020) impossible for so many. © 2020. Journal of International Women''s Studies.