Clinical Pharmacology & Therapeutics

BackgroundConcerns have been raised regarding the safety of Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) in patients with COVID-19, based on the hypothesis that such medications may raise expression of ACE2, the receptor for SARS-CoV-2. MethodsWe conducted a literature review of studies (n=12) in experimental animals and human subjects (n=12) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. ResultsThe findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses of ACEIs or ARBS than are typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. ConclusionAvailable evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID-19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended foetal harm. We investigate genetically proxied intrauterine antihypertensive exposure on offspring outcomes, including gestational age and birthweight, using two-sample multivariable Mendelian randomization. Higher levels of maternal protein targets for calcium channel blockers increased gestational age by 3.99 days (95%CI: 0.02, 7.96) per 10mmHg decrease in SBP. Genetically proxied maternal protein targets for beta-adrenoceptor blocking drugs, vasodilator antihypertensive drugs on the KNCJ11 gene, potassium-sparing diuretics and aldosterone antagonists demonstrated little evidence of increased risk to offspring. Both parental genetic protein targets for vasodilator antihypertensive drugs demonstrated similar effects on birthweight, suggesting detrimental offspring effects due to genetic perturbation of these pathways is unlikely. Little evidence for increased risk of adverse offspring outcomes due to maternal antihypertensive drug target perturbation was found. Triangulation of these findings with existing evidence may guide physicians and mothers during pregnancy.

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death from severe disease in non-hospitalized high-risk patients with mild-to-moderate COVID-19 following either intravenous (IV) or intramuscular (IM) administration. Population pharmacokinetic (popPK) and exposure-response (ER) analyses were performed to characterize sotrovimab PK and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following IV or IM administration. Sotrovimab PK was described by a two-compartment model with linear elimination; IM absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on IM bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final popPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 hours that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors ([≤]1 vs >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across SARS-COV-2 variants.

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe COVID-19, but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is an FDA approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modelling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase 1 trial in healthy adult participants was undertaken with high dose nitazoxanide. Participants received 1500mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose and schedule. Intensive pharmacokinetic sampling was undertaken day 1 and 5 with Cmin sampling on day 3 and 7. Fourteen healthy participants were enrolled between 18th February and 11th May 2021. All 14 doses were completed by 10/14 participants. Nitazoxanide was safe and well tolerated with no significant adverse events. Moderate gastrointestinal disturbance (loose stools) occurred in 8 participants (57.1%), with urine and sclera discolouration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on first dose and maintained throughout. Nitazoxanide administered at 1500mg BID with food was safe and well tolerated and a phase 1b/2a study is now being initiated in COVID-19 patients.

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI2) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION. MethodsSixteen healthy participants (19-61 years) were treated with celecoxib (100 mg every 12h), naproxen (250 mg every 12h), or placebo administered twice daily for seven days in a double-blind, crossover design randomized by order. On Day 7 when drug levels had reached steady state, the degree of COX inhibition was assessed ex vivo and in vivo. Ambulatory blood pressure was measured throughout the final 12h dosing interval. ResultsBoth NSAIDs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9{+/-}21.7%) than celecoxib (35.7{+/-}25.2%; p<0.05). Similarly, naproxen treatment inhibited PGI2 formation in vivo (48.0{+/-}24.9%) to a greater degree than celecoxib (26.7{+/-}24.6%; p<0.05). Naproxen significantly increased blood pressure compared to celecoxib (differences in least-square means of mean arterial pressure: 2.5 mm Hg (95% CI: 1.5, 3.5); systolic blood pressure: 4.0 mm Hg (95% CI: 2.9, 5.1); diastolic blood pressure: 1.8 mm Hg (95% CI: 0.8, 2.8); p<0.05 for all). The difference in systolic blood pressure relative to placebo was associated with the degree of COX-2 inhibition (p<0.05). ConclusionsCelecoxib 200 mg/day inhibited COX-2 activity to a lesser degree than naproxen 500 mg/day, resulting in a less pronounced blood pressure increase. While the PRECISION trial concluded the non-inferiority of celecoxib regarding cardiovascular risk, this is based on a comparison of doses that are not equipotent. ClinicalTrials.gov identifier: NCT02502006 (https://clinicaltrials.gov/study/NCT02502006) Clinical PerspectiveO_LINaproxen 250 mg twice a day inhibited COX-2 activity to a greater degree than celecoxib 100 mg twice a day. C_LIO_LIThe degree of COX-2 inhibition was associated with the increase in systolic blood pressure with NSAID treatment relative to placebo. C_LIO_LIDose and its pharmacological potency achieved in vivo should be considered when evaluating the relative cardiovascular safety of COX-2-selective vs. non-selective NSAIDs. C_LI

BackgroundDrug suitability is determined by safety, efficacy, and pathological appropriateness. The pharmacogenomics of drug suitability can be assessed by analyzing drug response and drug choice in large population cohorts. MethodsWe investigated drug response and drug choice for dyslipidemia and hypertension using genetic, phenotypic, and prescribing data from the UK Biobank and the All of Us Research Program. Drug response was reassessed with rigorous biomarker scaling, while genome-wide association studies (GWAS) and polygenic scores were used to examine genetic factors influencing drug choice. ResultsConventional analyses showed that variants influencing baseline LDL cholesterol (LDL-C) were inversely associated with absolute LDL-C change but concordant with relative change following statin therapy; these signals disappeared after applying a variance-stabilizing Box-Cox transformation, indicating a methodological artifact in biomarker scaling. GWAS for drug choice identified several significant loci and unique genetic correlation patterns with cardiometabolic traits. Polygenic scores for drug choice yielded statistically significant predictive performance, which was enhanced by incorporating demographic factors, though prediction strength in clinical settings remains modest. ConclusionVariance-stabilizing transformation corrects spurious pharmacogenetic associations introduced by biomarker scaling. Genetic variation informs drug choice for dyslipidemia and hypertension, but current polygenic scores provide only modest benefits in clinical application.

BackgroundThe SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs which up- or down-regulate ACE2 expression are therefore of critical research interest as agents which might promote or reduce risk of COVID-19 infection in a susceptible population. AimTo review evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2 and potentially affect COVID-19 infection. Design and settingSystematic review of studies published in MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science from inception to April 1st 2020. MethodA systematic review will be conducted in line with PRISMA guidelines. Inclusion criteria will be: i) assess effect of drug exposure on ACE2 level; ii) drug is included in British National Formulary (BNF) and therefore available to prescribe in UK; iii) a control, placebo or sham group is included as comparator. Exclusion criteria will be: i) ACE2 measurement in utero; ii) ACE2 measurement in children under 18 years; iii) drug not in BNF; iv) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYRCLE risk of bias tool for animal studies. ResultsData will be reported in summary tables and narrative synthesis. ConclusionThis systematic review will identify drug therapies which may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.

ObjectiveIn spite of evidence and recommendations reflecting the importance of pharmacogenomic testing, most prescriptions are still given without testing. We demonstrate the real world implications of the use of testing and evaluate adverse events and outcomes in individuals who did not receive pharmacogenomic testing for clopidogrel. MethodsWe analyzed ~100K individuals with paired EHR and exome sequencing data from population health studies administered at multiple medical centers using the Helix Exome+(R) assay. We inferred clopidogrel dosage by processing the prescription with an LLM. We identified all instances of individuals with at least one prescription that is not in concordance with their CYP2C19 genotype. Lastly, we identify instances of thrombosis using a comprehensive codeset based on ICD9, ICD10, and SNOMED terms. ResultsWe identified 16,140 prescriptions of clopidogrel given to 3,853 participants. We found that 29% of these individuals have a mismatch between the recommended clopidogrel dosage guideline based on their CYP2C19 genotype and their actual prescribed daily dosage. 25% of poor metabolizers experienced thrombosis, with 40% occurring within 2 months of treatment. Poor and intermediate metabolizers receiving clopidogrel are much more likely to experience thrombosis and myocardial infarction (binomial p-value = 0.001). ConclusionsWe estimate a 38% excess of adverse events occur in poor and intermediate metabolizers relative to normal and rapid metabolizers. The lack of testing may be responsible for 1 thrombosis event per every ~30 people prescribed clopidogrel.

IntroductionCaly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5M. The concentration resulting in 50% inhibition (IC50, 2 {micro}M) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted. MethodSimulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 g/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose. ResultsPlasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0857 {micro}M) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 {micro}M). ConclusionsThe likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.

Many drugs that have been proposed for treatment of COVID-19 are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here we explored the potential effects on cardiac electrophysiology of 4 drugs proposed to treat COVID-19: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PK) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both pharmacokinetic and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that females with pre-existing heart disease are especially susceptible to drug-induced arrhythmias, compared males with disease or healthy individuals of either sex. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID-19 therapies.

The risk-benefit ratio associated with the use of repurposed drugs to treat 2019 SARS-CoV-2 related infectious disease (COVID-19) is complicated since benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID-19. A risk assessment of drug-induced Long QT Syndrome (LQTS) associated with COVID-19 repurposed drugs was performed and compared to 23 well-known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Seven different LQTS indices were calculated and compared. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Estimators of LQTS risk levels indicated a very high or moderate risk for all COVID-19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug-induced LQTS for the 6 repurposed medications and 23 torsadogenic compounds. Based on our results, monitoring of the QT interval shall be performed when some COVID-19 repurposed drugs are used, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients.

The safety, tolerability, pharmacokinetics, age-related effects of single (SD) and repeat (RD) doses of CMS121, a novel small molecule fisetin derivative, were evaluated in healthy adult volunteers. The effects of food were also evaluated in healthy young adult subjects. SD of up to 1800 mg or RD up to 900 mg/day for 7 days was generally well tolerated, with the majority of TEAEs mild in severity. Generally, the pharmacokinetics of CMS121 and its metabolites were well characterized and increased in a dose-proportional or slightly greater than dose-proportional manner across the range of doses assessed. CMS121-C2 metabolite appears to contribute the most to the presence of the molar-equivalent CMS121 in plasma than the parent compound or the other metabolites (i.e. CMS121-C1 and CMS121-C3). Urinary excretion of CMS121 metabolites was minimal, implying urinary excretion may not be a major clearance route by which CMS121 is eliminated after oral dosing. There is a significant effect of age on the pharmacokinetics of CMS121 and its metabolites, with higher systemic exposures to CMS121 and its metabolites and longer terminal elimination half-lives in elderly subjects. Systemic exposures to CMS121 were higher in the fed state by approximately 50%.

AimsTo describe the 1-year direct and indirect transition probabilities to premature discontinuation of statin therapy after concurrently initiating statins and CYP3A4-inhibitor drugs. MethodsA retrospective new-user cohort study design was used to identify (N=160828) patients who concurrently initiated CYP3A4-inhibitors (diltiazem, ketoconazole, clarithromycin, others) and CYP3A4-metabolized statins (statin DDI exposed, n = 104774) vs. other statins (unexposed, n = 56054) from the MarketScan Commercial claims database (2012 - 2017). These groups were matched (2:1) through propensity score-matching techniques. We applied a multistate transition model to compare the 1-year transition probabilities involving four distinct states (start, adverse drug events [ADEs], discontinuation of CYP3A4-inhibitor drugs, and discontinuation of statin therapy) between those exposed to statin DDIs, vs. unexposed. Statistically significant differences were assessed by comparing the 95% confidence intervals (CIs) of probabilities. ResultsPatients exposed to statin DDIs, vs. unexposed, were significantly less likely to discontinue statin therapy (71.4 [95% CI: 71.1, 71.6] vs. 73.3 [95% CI: 72.9, 73.6]) but more likely to experience an ADE (3.4 [95% CI: 3.3, 3.5] vs. 3.2 [95% CI: 3.1, 3.3]) and discontinue with CYP3A4-inhibitor therapy (21.0 [95% CI: 20.8, 21.3] vs. 19.5 [95% CI: 19.2, 19.8]) directly after concurrently starting stains and CYP3A. Subsequent to experiencing an ADE, those exposed to statin DDIs were still less likely to discontinue statin therapy but were significantly more likely to discontinue CYP3A4-inhibitor therapy. ConclusionWhile statin DDI exposure was associated with higher likelihood of ADEs, this did not increase the risk of premature statin discontinuation among patients exposed to statin DDIs, versus unexposed.

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human administration of ClC-1 inhibitor NMD670. In this randomized, double-blind, placebo-controlled study we evaluated safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects. Single-ascending doses were administered in a (partial) cross-over design; multiple-ascending doses were administered in a parallel design. Differences in pharmacokinetics between males/females and fed/fasted state were evaluated. Pharmacodynamic effects were evaluated using muscle velocity recovery cycles (MVRC), and analyzed using mixed effects modelling, with baseline as covariate. NMD670 was considered safe and well-tolerated. Symptoms of myotonia were observed at the highest dose levels. Moreover, NMD670 significantly increased the following MVRC parameters after a single dose of 1200mg compared to placebo: early supernormality (estimated difference (ED) 2.04; 95% confidence interval (CI) (0.379, 3.70); p=0.0242); early supernormality after 5 conditioning stimuli (ED 2.51; 95%CI (0.599, 4.41); p=0.0177; supernormality at 20 ms (ED 2.78; 95%CI (1.377, 4.181); p=0.0021. Importantly, the results of this study indicate pharmacological target engagement of NMD670 as ClC-1 inhibitor, at dose levels that were considered safe in healthy subjects. Firstly, because myotonia was an expected exaggerated on-target pharmacological effect. Secondly, because the effects on MVRC indicate increased muscle cell excitability. This study in healthy subjects indicates proof-of-mechanism and provides a solid base for translation to patients with neuromuscular diseases.

Based on early reports of the efficacy of hydroxychloroquine sulfate (HCQS) to inhibit SARS-CoV-2 viral replication in vitro, and since severe pulmonary involvement is the major cause of COVID-19 mortality, we assessed the safety and efficacy of aerosolized HCQS (aHCQS) therapy in animals and humans. In a Phase 1 study of aHCQS in healthy volunteers, doses up to 50 mg were well tolerated and estimated epithelial lining fluid concentrations immediately after inhalation (>2,000 M) exceeded the in vitro concentrations needed for suppression of viral replication ([&ge;]119 M). A study in rats comparing HCQS solution administered orally (13.3 mg/kg) and by intratracheal installation (IT 0.18 mg/kg, <5% of oral dose) demonstrated that at 2 minutes, IT administration was associated with 5X higher mean hydroxychloroquine (HCQ) concentrations in the lung (IT: 49.5 {+/-} 6.5 {micro}g HCQ/g tissue, oral: 9.9 {+/-} 3.4; p<0.01). A subsequent study of IT and intranasal HCQS in the Syrian hamster model of SARS-CoV-2 infection, however, failed to show clinical benefit. We conclude that aHCQS alone is unlikely to be effective for COVID-19, but based on our aHCQS pharmacokinetics and current viral entry data, adding oral HCQS to aHCQS, along with a transmembrane protease inhibitor, may improve efficacy.

BackgroundConcerns have been expressed about a number of drugs that potentially worsen outcomes in patients with COVID-19. We sought to identify all potentially deleterious drug groups in COVID-19 and critically assess the underpinning strength of evidence pertaining to the harmful effects of these drugs. Methods and findingsWe performed a rapid systematic review, searching Medline, Embase and two COVID-19 portfolios (WHO COVID-19 database and NIH iSearch COVID-19 portfolio) for papers and preprints related to primary studies investigating drugs identified as potentially deleterious. Primary outcomes were direct measures of susceptibility to infection, disease severity and mortality. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tools. Random-effects meta-analyses were used for data synthesis with further subgroup analyses where possible for specific outcome, study design, statistical adjustment and drug groups when two were combined. Sensitivity analyses were performed by removing any studies at high risk of bias and by publication status. 49 observational studies (15 peer-reviewed papers and 34 preprints) reported primary outcomes for eight drug groups hypothesised to be deleterious. Meta-analysis showed that acute inpatient corticosteroid use was associated with increased mortality (OR 2.22, 95% CI 1.26-3.90), however this result appeared to have been biased by confounding via indication. One subgroup analysis indicated an association between immunosuppressant use and susceptibility to COVID-19 among case control and cross-sectional studies (OR 1.29, 95% CI 1.19-1.40) but this was not found with cohort studies (OR 1.11, 95% CI 0.86-1.43). Studies which adjusted for multiple confounders showed that people taking angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) required a lower level of care (OR 0.85, 95% CI 0.74-0.98). Furthermore, studies which combined these two drug groups in their analysis demonstrated an association with a lower mortality (OR 0.68, 95% CI 0.55-0.85). ConclusionsWe found minimal high quality or consistent evidence that any drug groups increase susceptibility, severity or mortality in COVID-19. Converse to initial hypotheses, we found some evidence that regular use of ACEIs and ARBs prior to infection may be effective in reducing the level of care required, such as requiring intensive care, in patients with COVID-19.

BackgroundCovid-19 is associated with respiratory-related morbidity and mortality. Angiotensin receptor blockers (ARB) have been postulated as tentative pharmacological agents to treat Covid-19-induced inflammation. MethodsThis is a randomized, two-arm, open, multicenter trial. Participants were 18 years or older and had been hospitalized with confirmed Covid-19 with 4 or fewer days since symptom onset. Exclusion criteria included intensive care unit admission prior to randomization and ARB or angiotensin converting enzyme inhibitors use. Treatment arm received telmisartan 80 mg bid during 14 days plus standard care; control arm received standard care. Primary outcome were differences in C-reactive protein levels at days 5 and 8. Secondary outcomes included time to discharge evaluated at 15 days and death at 30 days post randomization. ResultsThis interim analysis included 40 patients in telmisartan and 38 in control groups. CRP levels in the control and telmisartan groups were 51.1{+/-}44.8 mg/L vs 24.2{+/-}31.4 mg/L at day 5 (mean {+/-} SD; n=28 and n=32, p<0.05), and 41.6{+/-}47.6 mg/L vs 9.0{+/-}10.0 mg/L at day 8 (mean {+/-} SD; n=16 and n=13; p<0.05), respectively. Telmisartan treated patients had statistically significant lower time to discharge (log-rank test p=0.0124, median time: 15 days in control group vs 9 days in telmisartan group). Mortality at day 30 was 11.76% in control group vs 5.26% in telmisartan group (p=0.41). ConclusionsIn this study, ARB telmisartan, a well-known inexpensive safe antihypertensive drug, administered in high doses, was superior to standard care demonstrating anti-inflammatory effects and improved morbidity in hospitalized patients infected with SARS-CoV-2 (NCT04355936).

BackgroundCoronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP). MethodsLPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. ResultsThe median age of study participants was 59 (range 24-85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4-10) and 8 days (IQR 5-10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 g/mL (IQR 18.9-31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p<0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values. ConclusionsHigh LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.

ObjectiveTo establish an optimized sotalol dosing strategy for fetal tachycardia by using a pregnancy computational model for dose simulations. MethodsA physiologically-based computational model, including pregnancy-related changes and placental transfer values, was established and verified. Simulations of the current dosing advises and prospective dosing scenarios were performed. To avoid maternal dose-related toxicity (QT-prolongation) we aimed for maternal concentrations <2.5 mg/L. Based on neonatal concentration-effect data, we aimed for a fetal Ctrough concentrations of 0.4 - 1.0 mg/L. ResultsThe pregnancy physiologically-based pharmacokinetic model accurately predicted maternal and fetal exposures. Predictions indicate that almost 16% of maternal plasma concentrations exceed the toxic level of 2.5 mg/L at the maximum oral daily dose of 480 milligram, while 90% of fetuses have a Ctrough concentration within the therapeutic window. When lowering the maximum daily dose to 400 mg, 0.1% of maternal plasma concentrations exceed 2.5 mg/L, while 87% of the fetal plasma concentrations remain in the therapeutic window. Additionally dosing 480 mg in three times daily reduces the risk of high maternal plasma exposure to 0.3%, while maintaining effective fetal Ctrough concentrations in 95% of fetuses. ConclusionPregnancy computational modeling can be used to adequately predict maternal and fetal sotalol exposures. Our simulations suggest that daily doses should not exceed 400 milligram and that dividing the oral daily dose over three doses improves the balance between high maternal plasma exposure and effective fetal concentrations. FundingThis publication is based on research funded by the Bill & Melinda Gates Foundation (INV-023795).