This open-label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug-drug interaction between rilzabrutinib and quinidine (an inhibitor of P-glycoprotein [P-gp] and CYP2D6) or rifampin (an inducer of CYP3A and P-gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash-out period, after co-administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0-∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P-gp.

Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalizations and mortality. Lumicitabine, an oral nucleoside analog was studied for the treatment of RSV. The phase 1b and phase 2b studies reported here assessed the safety, pharmacokinetics, and pharmacodynamics of lumicitabine in infants/neonates hospitalized with RSV. In the phase 1b study, infants (≥1 to ≤12 months) and neonates (<28 days) received a single-ascending or multiple-ascending doses (single loading dose [LD] then 9 maintenance doses [MD] of lumicitabine, or placebo [3:1]). In the phase 2b study, infants/children (28 days to ≤36 months old) received lumicitabine 40/20 mg/kg, 60/40 mg/kg LD/MD twice-daily or placebo (1:1:1) for 5 days. Safety, pharmacokinetics, and efficacy parameters were assessed over 28 days. Lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. Plasma levels of ALS-008112, the active nucleoside analog, were dose-proportional with comparable mean exposure levels at the highest doses in both studies. There were no significant differences between the lumicitabine groups and placebo in reducing viral load, time to viral non-detectability, and symptom resolution. No emergent resistance-associated substitutions were observed at the RSV L-gene positions of interest. In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia and failed to demonstrate antiviral activity in RSV-infected hospitalized infants. This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b).

Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated small-interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half-life, but long duration of effects on PCSK9 inhibition and low-density lipoprotein cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent LDL-C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic-pharmacodynamic (K-PD) model was developed to characterize inclisiran's dose-related LDL-C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL-C lowering. To accommodate the long duration of action, the K-PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL-C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL-C. The analysis of covariates identified PCSK9 and LDL-C baseline levels as important factors for the effects of LDL-C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL-C reductions are achieved rapidly after dosing and sustained when patients are treated with a 300 mg s.c. dose once every 6 months.

This single‐center, open‐label, non‐randomized, two‐part, phase I study was conducted (1) to evaluate the absolute oral bioavailability of rilzabrutinib 400 mg tablet following an i.v. microtracer dose of ~100 μg [14C]‐rilzabrutinib (~1 μCi) and single oral dose of 400 mg rilzabrutinib tablet (part 1), and (2) to characterize the absorption, metabolism, and excretion (AME) of 14C‐radiolabeled rilzabrutinib following single oral dose (300 mg) of [14C]‐rilzabrutinib (~1000 μCi; administered as a liquid) in healthy male participants (part 2). A total of 18 subjects were enrolled (n = 8 in part 1; n = 10 in part 2). The absolute bioavailability of 400 mg rilzabrutinib oral tablet was low (<5%). In part 1, rilzabrutinib was absorbed rapidly after single oral dose of rilzabrutinib 400 mg tablet with a median (range) time to maximum concentration (Tmax) value of 2.03 h (1.83–2.50 h). The geometric mean (coefficient of variation) terminal half‐life following the oral dose and i.v. microtracer dose of ~100 μg [14C]‐rilzabrutinib, were 3.20 (51.0%) and 1.78 (37.6%) h, respectively. In part 2, rilzabrutinib was also absorbed rapidly following single oral dose of 300 mg [14C]‐rilzabrutinib solution with a median (range) Tmax value of 1.00 h (1.00–2.00 h). The majority of total radioactivity was in the feces for both non‐bile collection subjects (92.9%) and bile collection subjects (87.6%), and ~5% of radioactivity was recovered in urine after oral administration. Urinary excretion of unchanged rilzabrutinib was low (3.02%). The results of this study advance the understanding of the absolute bioavailability and AME of rilzabrutinib and can help inform its further investigation.

BACKGROUND: Inclisiran, a small interfering RNA molecule, reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting production of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver.OBJECTIVE: To investigate the pharmacokinetics, pharmacodynamics, and safety of inclisiran in patients with mild or moderate hepatic impairment (HI) vs participants with normal hepatic function (NHF). METHODS: In this single-center, open-label, parallel-group study, patients with mild (Child-Pugh A) or moderate (Child-Pugh B) HI and with NHF, matched by age, body mass index, sex, and race (if possible), received a single subcutaneous therapeutic dose of inclisiran (300 mg). Pharmacokinetic profiles, pharmacodynamic endpoints (PCSK9 and LDL-C), and safety were assessed. RESULTS: Twenty-eight participants completed the study (mild HI: n = 10; moderate HI: n = 6; NHF: n = 12). Inclisiran achieved maximum plasma concentration at 4-6 h and was undetectable in plasma at 48 h in most participants, irrespective of liver function. Inclisiran exposure was 1.24-fold higher in the mild HI vs NHF groups (90% confidence interval [CI] 1.01-1.53) and 2.03-fold higher in the moderate HI vs NHF groups (90% CI 1.60-2.58). LDL-C and PCSK9 plasma levels decreased from baseline up to the last assessment on Day 60 in all groups, with a similar response in NHF and mild HI groups but a less pronounced and more varied decrease in the moderate HI group. Inclisiran was generally safe and well tolerated. CONCLUSION: The pharmacokinetic exposure of inclisiran increased by up to two fold in patients with moderate HI compared with those with NHF, while pharmacodynamic effects remained relatively unchanged. Inclisiran is generally safe and well tolerated in patients with mild or moderate HI, with no dose adjustment needed. However, a larger, long-term clinical trial would help to further evaluate the long-term safety profile of inclisiran in patients with liver disease. (c) 2022 National Lipid Association. Published by Elsevier Inc.

To assess the combined role of anti‐viral monoclonal antibodies (mAbs) and vaccines in reducing severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) transmission and mortality in the United States, an agent‐based model was developed that accounted for social contacts, movement/travel, disease progression, and viral shedding. The model was calibrated to coronavirus disease 2019 (COVID‐19) mortality between October 2020 and April 2021 (aggressive pandemic phase), and projected an extended outlook to estimate mortality during a less aggressive phase (April–August 2021). Simulated scenarios evaluated mAbs for averting infections and deaths in addition to vaccines and aggregated non‐pharmaceutical interventions. Scenarios included mAbs as a treatment of COVID‐19 and for passive immunity for postexposure prophylaxis (PEP) during a period when variants were susceptible to the mAbs. Rapid diagnostic testing paired with mAbs was evaluated as an early treatment‐as‐prevention strategy. Sensitivity analyses included increasing mAb supply and vaccine rollout. Allocation of mAbs for use only as PEP averted up to 14% more infections than vaccine alone, and targeting individuals ≥ 65 years averted up to 37% more deaths. Rapid testing for earlier diagnosis and mAb use amplified these benefits. Doubling the mAb supply further reduced infections and mortality. mAbs provided benefits even as proportion of the immunized population increased. Model projections estimated that ~ 42% of expected deaths between April and August 2021 could be averted. Assuming sensitivity to mAbs, their use as early treatment and PEP in addition to vaccines would substantially reduce SARS‐CoV‐2 transmission and mortality even as vaccination increases and mortality decreases. These results provide a template for informing public health policy for future pandemic preparedness.

Abstract Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low‐density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double‐blind, double‐dummy, placebo‐ and positive‐controlled, three‐way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7‐day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo‐ and baseline‐corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST‐ and T‐wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran.

Abstract This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two‐part phase I study (anzctr.org.au ACTRN12618001036202). Part A was a randomized, open‐label, three‐period, single‐dose crossover study (n = 12) with rilzabrutinib 100 mg ± ritonavir 100 mg or rilzabrutinib 1200 mg. Part B was a randomized, double‐blind, placebo‐controlled, four‐way, single‐dose crossover study (n = 39) with matched placebo, rilzabrutinib 400 mg ± ritonavir 100 mg, or moxifloxacin (positive control). Primary objectives: part A – pharmacokinetics (PK) of rilzabrutinib ± ritonavir, safety, and optimal dose for Part B; Part B – effect of rilzabrutinib therapeutic and supratherapeutic concentration on electrocardiogram (ECG) parameters. ECGs and PK samples were serially recorded before and post‐dose. In part A, rilzabrutinib 100 mg + ritonavir led to 17‐fold area under the concentration–time curve (AUC0–∞) and 7‐fold maximum plasma concentration (Cmax) increases over rilzabrutinib alone. Rilzabrutinib 1200 mg was discontinued due to mild‐to‐moderate gastrointestinal intolerance. In Part B, rilzabrutinib 400 mg + ritonavir increased rilzabrutinib mean AUC0–∞ from 454 to 3800 ng h/mL and Cmax from 144 to 712 ng/mL. The concentration–QTc relationship was slightly negative, shallow (−0.01 ms/ng/mL [90% CI −0.016 to −0.001]), and an effect >10 ms on QTcF could be excluded within the observed range of plasma concentrations, up to 2500 ng/mL. Safety was similar to other studies of rilzabrutinib. In conclusion, rilzabrutinib, even at supratherapeutic doses, had no clinically relevant effects on ECG parameters, including the QTc interval.

Access lag to innovative therapies in Asian populations continues to present a challenge to global health. Recent progressive changes in the global regulatory landscape, including newer guidelines, are enabling simultaneous global drug development and near-simultaneous global drug registration. The International Conference on Harmonization (ICH) E17 guideline outlines general principles for the design and analysis of multiregional clinical trials (MRCTs). We posit that translational research and quantitative clinical pharmacology tools are core enablers for Asia-inclusive global drug development aligned with ICH E17 principles. Assessment of ethnic sensitivity should be initiated early in the development lifecycle to inform the need for, and extent of, Asian phase I ethno-bridging data. Relevant ethno-bridging data may be generated as standalone Asian phase I trials, as part of Western First-In-Human trials, or under accelerated development settings as a lead-in phase in an MRCT. Quantitative understanding of human clearance mechanisms and pharmacogenetic factors is vital to forecasting ethnic sensitivity in drug exposure using physiologically-based pharmacokinetic models. Stratification factors to control heterogeneity in MRCTs can be identified by reverse translational research incorporating pharmacometric disease models and model-based meta-analyses. Because epidemiological variations can extend to the molecular level, quantitative systems pharmacology models may be useful in forecasting how molecular variation in therapeutic targets or pathway proteins across populations might impact treatment outcomes. Through prospective evaluation of conservation in drug- and disease-related intrinsic and extrinsic factors, a pooled East Asian region can be implemented in Asia-inclusive MRCTs to maximize efficiency in substantiating evidence of benefit-risk for the region at-large with a Totality of Evidence approach.

SummaryBackgroundAntiviral monoclonal antibodies (mAbs) developed for treatment of COVID-19 reduce the magnitude and duration of viral shedding and can thus potentially contribute to reducing transmission of the causative virus, severe acute respiratory coronavirus 2 (SARS-CoV-2). However, use of these mAbs in combination with a vaccine program has not been considered in public health strategic planning.MethodsWe developed an agent-based model to characterize SARS-CoV-2 transmission in the US population during an aggressive phase of the pandemic (October 2020 to April 2021), and simulated the effects on infections and mortality of combining mAbs as treatment and post-exposure prophylaxis (PEP) with a vaccine program plus non-pharmaceutical interventions. We also interrogated the impact of rapid diagnostic testing, increased mAb supply, and vaccine rollout.FindingsAllocation of mAbs as PEP or targeting those ≥65 years provided the greatest incremental benefits relative to vaccine in averting infections and deaths, by up to 17% and 41%, respectively. Rapid testing, facilitating earlier diagnosis and mAb use, amplified these benefits. The model was sensitive to mAb supply; doubling supply further reduced infections and mortality, by up to two-fold, relative to vaccine. mAbs continued to provide incremental benefits even as proportion of the vaccinated population increased.InterpretationUse of anti-viral mAbs as treatment and PEP in combination with a vaccination program would substantially reduce SARS-CoV-2 transmission and pandemic burden. These results may help guide resource allocation and patient management decisions for COVID-19 and can also be used to inform public health policy for current and future pandemic preparedness.FundingRegeneron Pharmaceuticals.

Abstract Bruton’s tyrosine kinase (BTK), expressed in B cells and cells of innate immunity, including microglia, is an essential signaling element downstream of the B‐cell receptor and Fc‐receptors. Tolebrutinib (PRN2246, SAR442168) is a potent BTK inhibitor that covalently binds the kinase, resulting in durable inhibition with the potential to target inflammation in the periphery and central nervous system (CNS). Tolebrutinib crosses the blood‐brain barrier and potently inhibits BTK in microglial cells isolated from the CNS. A first‐in‐human randomized, double‐blind, placebo‐controlled study of tolebrutinib was conducted. The trial design consisted of five single ascending dose arms with oral administration of a single dose of 5, 15, 30, 60, and 120 mg (n = 6 per arm, n = 2 placebo), five multiple ascending dose arms with oral administration of 7.5, 15, 30, 60, and 90 mg (n = 8 per arm, n = 2 placebo) over 10 days, and one arm (n = 4) in which cerebral spinal fluid (CSF) exposure was measured 2 h after a single 120 mg dose. Tolebrutinib was well‐tolerated in the study and all treatment‐related treatment emergent adverse events were mild. Tolebrutinib was rapidly absorbed following oral administration with a rapid half‐life of ~ 2 h. Peripheral BTK occupancy was assessed at various timepoints by an enzyme‐linked immunosorbent assay‐based readout using an irreversible probe. Assessments demonstrated extensive and prolonged peripheral BTK occupancy at steady‐state with once daily doses as low as 7.5 mg. Further, CSF exposure was demonstrated 2 h after administration at 120 mg.

Model‐informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti‐infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug‐drug interactions. Examples are presented for state‐of‐the‐art, empiric, mechanistic, interdisciplinary, and real‐world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration‐based models, mechanism‐based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; “depth” and “breadth” of MIDD methods. “MIDD depth” refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired‐resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. “MIDD breadth” refers to greater adoption of model‐centered approaches to anti‐infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway.

Decentering is a ubiquitous therapeutic concept featuring in multiple schools of psychological intervention and science. It describes an ability to notice to day-to-day psychological stressors (negative thoughts, feelings, and memories) from an objective self-perspective and without perseverating on the themes they represent. Thus, decentering dampens the impact and distress associated with psychological stressors that can otherwise increase mental ill health in vulnerable individuals. Importantly, the strengthening of decentering-related abilities has been flagged as a core component of psychological interventions that treat and prevent anxiety and depression. We provide an in-depth review evidence of the salutary effects of decentering with a special focus on youth mental health. This is because adolescence is a critical window for the development of psychopathology but is often under-represented in this research line. A narrative synthesis is presented that integrates and summarizes findings on a range of decentering-related abilities. Section 1 reviews extant conceptualizations of decentering and data-driven approaches to characterize its characteristic. A novel definition is then offered to guide future empirical research. Section 2 overviews laboratory-based research into the development of decentering as well as its relationship with anxiety and depression. Section 3 examines the role decentering-related skills play in psychological interventions for anxiety and depression. Critically, we review evidence that treatment-related increases in decentering predict latter reductions in anxiety and depression severity. Each section highlights important areas for future research. The report concludes by addressing the vital questions of whether, how, why and when decentering alleviates youth anxiety and depression.

Post-traumatic stress disorder (PTSD) experienced by children can have a large impact on the wider family. The National Institute for Health and Care Excellence (NICE, 2018) recommend that parents are involved in their child’s PTSD treatment. Studies have found that parents themselves also report high levels of PTSD and other mental health symptoms but few have explored whether these symptoms reduce following their child receiving trauma-focused CBT. In this study, parents (N=29) whose children (ages 8-17 years) were randomly assigned to either 10 sessions of Cognitive Therapy for PTSD (CT-PTSD) or a wait-list control condition (WL) completed the Post Traumatic Stress Diagnostic Scale (PDS), the Patient Health Questionnaire (PHQ-9; to measure depression), the Generalised Anxiety Disorder Questionnaire (GAD-7), and the General Health Questionnaire (GHQ-28; to measure general mental health) for pre-post comparison. Parents whose children were allocated to CT-PTSD reported greater improvements on self-report PTSD, depression, anxiety and general mental health, relative to the WL condition. This trial provides preliminary support for the efficacy of CT-PTSD delivered to children for reducing parent PTSD, depression, anxiety and general mental health symptoms. Replication is needed as well as further exploration of parent factors and frequency of parental involvement required to predict improvements.

As new treatment modalities are being explored for SARS-CoV-2, efforts to repurpose existing marketed drugs remain an attractive option, as these agents are readily available and have a known safety profile. It is important to recognize that these drugs have not been specifically developed or optimized for the treatment of SARS-CoV-2 infected patients. Success in repurposing efforts will depend on being mindful of first principles around clinical pharmacology and dosing strategies, noting that the dose regimens of existing drugs were developed for different indications. 'Getting the dose right' for antivirals being targeted against acute respiratory viruses requires knowledge of potency, pharmacokinetics and viral kinetics to guide rational use. This commentary aims to review those principles of clinical pharmacology that are critical to the successful design and implementation of an optimal dosing regimen for drugs repurposed against SARS-CoV-2, using lopinavir/ritonavir (LPV/r) as an example. We selected LPV/r as it is being considered for the treatment of SARS-CoV-2; however, the standard dosing regimen may not be optimal for this new indication. Antiviral treatment must be initiated in an infected patient as soon as possible. This limited window to initiate antiviral therapy against respiratory viruses is well known. For example, if treatment of influenza is not initiated within 48–72 h of symptom onset, drug efficacy is substantially reduced or eliminated entirely.1 This treatment window can be defined by the viral kinetic profile of the pathogen, and corresponds to the time of peak viral load for an individual patient,2 and generally occurs prior to the onset of the so-called proinflammatory cytokine storm3 which is associated with severe disease and poor clinical outcome. If treatment of a patient is initiated after peak viral load or after the onset of the cytokine storm, any antiviral is unlikely to be effective. The viral kinetic profile varies by respiratory virus, with respiratory syncytial virus (RSV) having a longer time to peak and more prolonged duration of viral shedding compared to influenza.4 The viral kinetic profile of SARS-CoV-2 is not yet well understood, but initial data suggest that the time to peak appears to occur approximately 8–10 days after infection, or 5 days post onset of symptoms (See Supporting Information). This would indicate a 3- to 5-day treatment opportunity from the time of symptom onset. Similarly, the length of treatment should cover the duration of viral shedding to maximize drug effect, reduce the risk of viral rebound and to minimize the spread to uninfected individuals. SARS-CoV-2 appears to maintain a longer duration of viral shedding compared to influenza, and therefore a longer treatment duration may be warranted (e.g., 14 to 28 days). Even longer treatment durations may be required in immunocompromised patients. Given the limited treatment window to successfully intervene, it is paramount that antiviral dose regimens be constructed to achieve high therapeutic concentrations at the effect site as rapidly as possible. This has prompted numerous antivirals for respiratory pathogens to consider loading doses. A loading dose may achieve therapeutic concentrations much more quickly, increasing the probability of successful treatment. For existing antivirals like LPV/r, pharmacokinetic models can be leveraged via simulation to design an optimal loading dose regimen. Repurposing a drug already in clinical use provides reassurance that the safety profile is already established. For drugs like LPV/r, there is extensive clinical experience from decades of use in the treatment of patients with HIV, including use in special populations such as children, pregnant women and patients with hepatic impairment. However, it is important to remember that its clinical use was studied in a different patient population under a different treatment paradigm. LPV/r is generally considered to be 'well tolerated' in comparison to other long-term HIV treatment options, but gastrointestinal disorders (e.g., nausea, vomiting and diarrhoea) are common side effects, and there is little experience with the use of LPV/r and other HIV treatments in the elderly population with co-morbidities who may be most at risk from COVID-19. Any repurposing activities therefore need to include a benefit:risk evaluation focused on the new proposed clinical application. Little publically available potency information has been reported for any repurposed drug against SARS-CoV-2, to our knowledge. Therefore, antiviral activity must generally be inferred from studies of related human coronaviruses, which is a current limitation in the repurposing efforts. In addition, usually an IC50 or EC50 is reported in the literature, whereas a more aggressive target such as EC90 may be more clinically appropriate. For lopinavir, in the absence of human serum, the EC50 against HIV-1 ranges from 0.006 to 0.017 μg/ml, whereas in the presence of 50% human serum, the EC50 is approximately 10-fold higher (0.04–0.18 μg/ml), representing the significant impact of plasma protein binding on potency. While published reports for SARS-CoV-2 are not available, in vitro potency for related coronaviruses are assumed to be similar. The published IC50s or EC50s in the absence of human serum (i.e., unbound drug) for LPV for SARS or and MERS viruses have been reported to range from 4 to 15 μg/ml (see Supporting Information). The in vitro potency of LPV against coronaviruses would suggest that LPV may be more than 100 times less active against SARS-CoV-2 compared to HIV-1. Therefore, higher drug exposures and possibly a new dose regimen may be required to successfully treat coronaviruses with LPV/r. A basic principle of clinical pharmacology is that only free (unbound) drug is available to bind to the target or to distribute to the site of action, as drug bound to plasma proteins is sequestered and otherwise inaccessible. Like most HIV protease inhibitors, LPV demonstrates very high protein binding, being approximately 98.5% bound (1.5% free). Therefore, in considering whether a dose is appropriate for SARS-Cov-2, it is critical to consider free drug concentrations. For LPV, the steady-state total minimum plasma concentration (Cmin) at the standard HIV-1 treatment dose of 400/100 mg LPV/r is approximately 5 μg/ml, or 0.075 μg/ml of unbound (free) drug. This is a sufficient concentration to cover HIV-1 but is substantially below the 4–15 μg/ml EC50 reported for coronaviruses. It is important to consider drug concentrations at the site of infection, and currently, the lack of robust lung penetration data is an important gap that exists for many agents being considered for repurposing. In the absence of data, physiologically based pharmacokinetic (PBPK) modelling can be used to predict lung exposures, as it has been done for hydroxychloroquine.5 This work by Yao and colleagues for hydroxychloroquine demonstrates a potential framework for drug repurposing, via the generation IC50s against related coronaviruses, and use of PBPK to design a loading and maintenance dose regimen specifically targeted towards SARS-CoV-2 in the lung. In the case of LPV, lung penetration is complex and not well understood; however, typically it is the plasma free fraction that is available to penetrate into tissues. Therefore, given its potency, lung penetration of LPV would have to be high to provide concentrations in the therapeutic range. There are two case reports of LPV/r lung concentrations in HIV patients, and it appears that the ELF:plasma exposure of lopinavir may be up to 2-fold (~1.6 μg/ml) at standard doses. Given the uncertainty around LPV/r lung penetration, additional data are required to understand for certain if very high doses might be sufficient to reach therapeutic exposures in the lung. An important further goal of dose optimization is to ensure that most patients in the population, treated with a common dose regimen, will achieve therapeutic drug concentrations. Lopinavir demonstrates high pharmacokinetic variability, which means that doses will need to be relatively high to ensure a common dose regimen will achieve therapeutic concentrations in the majority of patients. Population PK modelling can be utilized to simulate exposures across a range of patients, to ensure that the majority of the target population will achieve target concentrations. The above ideas are synthesized using LPV/r as a case study for SARS-CoV-2. We utilized published population pharmacokinetic models that characterize the plasma exposures of LPV/r, incorporating the clinical pharmacology concepts noted above (see Supporting Information). We have thus used these models to simulate LPV plasma (total and unbound) and lung (ELF) exposures in an adult population and compared them to in vitro potency against SARS-CoV and MERS-CoV, to evaluate the potential of LPV as an effective antiviral for SARS-CoV-2 (Figure 1). These results suggest that the unbound plasma concentrations of LPV remain very low relative to the available EC50s. While limited data are available to inform the lung exposures, it may be possible to reach therapeutic exposures in some patients with higher doses. It is also important to note that the time to achieve high concentrations of LPV takes several days, which would suggest that a loading dose would be necessary to maximize any potential treatment effect. Based on the results of our assessment, standard LPV/r doses are at high risk of treatment failure. The time to reach full concentrations takes 36–48 h in the absence of a loading dose, hence losing valuable time in the treatment window. Doses of LPV/r are also limited by safety and tolerability, with significant GI-related adverse events, potential for QTc prolongation and substantial drug–drug interactions. To date, a number of animal and clinical trials have failed to show a benefit of LPV/r in coronaviruses, including most recently a large trial in severe hospitalized patients,6 and a small trial in mild-to-moderate hospitalized patients.7 The large study by Cao et al. evaluated a very challenging patient population, and standard dose LPV/r was initiated late in the disease course, likely too late for there to be benefit. In all likelihood, no antiviral was likely to be effective in this difficult-to-treat population, particularly using the LPV/r dosing regimen that was optimized for HIV infection. The results of this study confirm that late treatment with standard doses of LPV/r are unlikely to have benefit for COVID-19. Li et al reported no LPV/r treatment effect in a small cohort of approximately 21 mild-to-moderate hospitalized patients, with a mean (range) start time of 4.3 days post symptom onset using standard dose LPV/r.7 Based on these studies, there is growing evidence that current approaches using standard LPV/r treatment for hospitalized patients are not effective, which is consistent with the clinical pharmacology data. This commentary highlights the critical need for the collection and sharing of the key data, which will be required to prioritize and evaluate potential repurposed drug candidates, and to design COVID-19 targeted dosing paradigms which specifically address the unique challenges associated with treating this disease. While there are uncertainties regarding the likelihood of achieving effective concentrations in the lung with LPV/r, it is clear that the delay in time before plasma concentrations achieve the effective EC50 levels decreases the opportunity for the standard dosing regimen to effectively block virus replication until many days after instituting therapy. If rapid viral inhibition is the purpose of implementing this therapy, then early aggressive intervention with the use of loading doses will be necessary, which could impact tolerability. The use of clinical pharmacology and model-based dosing design will be important to maximize the likelihood of successful deployment of existing antiviral drugs for COVID-19 and future pandemics. The authors acknowledge the helpful input, discussions and review of Steve Kern, Dan Hartman, Mark Milad and Terrence Blashke. Funding was provided in part by the Bill and Melinda Gates Foundation. PFS, DB and CR wrote and edited the manuscript, and MD and KY conducted the modelling and data analysis. The authors report no conflict of interest. Data S1. Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Perhaps the most important lesson learned from the COVID-19 pandemic is that of preparedness. Enhanced surveillance systems for early threat detection will be crucial to maximizing response time for implementation of public health measures and mobilization of resources in containing an emerging pandemic. Recent outbreaks have been dominated by viral pathogens, with RNA respiratory viruses being the most likely to have pandemic potential. These should therefore be a preparedness priority. Tools in the areas of virology, drug discovery, clinical pharmacology, translational medicine and pharmacometrics should be considered key components in the rapid identification and development of existing and novel interventions for a pandemic response. Prioritization of therapeutics should be based on in vitro activity, likelihood of achieving effective drug concentrations at the site of action, and safety profile at the doses that will be required for clinical efficacy. Deployment strategies must be tailored to the epidemiology of the disease, and the adequacy of the response should be re-evaluated in view of evolving epidemiological factors. An interdisciplinary framework integrating drug pharmacology, viral kinetics, epidemiology and health economics could help optimize the deployment strategy by improving decision-making around who to treat, when to treat, and with what type of intervention for optimal outcomes. Lastly, while an effective vaccine will ultimately end a pandemic, antiviral drug intervention guided by clinical pharmacology principles will continue to play a critical role in any pandemic response.