Dosing will be a key success factor in repurposing antivirals for COVID‐19

Abstract

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.

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