Abdallah Derbalah

and 4 more

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug-target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended provide a guide to modellers in their model endeavours to simplify these complicated models.

Ricardo Pena Silva

and 5 more

Hundreds of researchers are working to develop a vaccine and are evaluating drugs to mitigate the adverse health and economic consequences of COVID-19 (Coronavirus disease 19) worldwide. If novel compounds are found, geopolitical and economic variables will determine their introduction to communities. Therefore, finding low-cost and widely accessible drugs for prevention or treatment of COVID-19 would be ideal.A recent study found that ivermectin, an FDA-approved anti-parasitic drug, has inhibitory effects on replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Ivermectin has broad anti-viral activity through inhibition of viral proteins including importin α/β1 heterodimer and integrase protein2. Caly and colleagues reported that the addition of ivermectin at a concentration of 5 micromolar (μM) (twice the reported IC50) to Vero-hSLAM cells, 2 hours post infection with SARS-CoV-2, resulted in a reduction in the viral RNA load by 99.98% at 48 hours1. The authors suggested that this drug could reduce the viral load in infected patients, with potential effect on disease progression and spread.While the findings by Caly and colleagues provide some promise, there is no evidence that the 5 μM concentration of ivermectin used by Caly and colleagues in their in vitro SARS-CoV-2 experiment, can be achieved in vivo . The pharmacokinetics of ivermectin in humans is well described (Figure 1)3-5, and even with the highest reported dose of approximately 1700 µg/kg (i.e. 8.5 times the FDA-approved dose of 200 μg/kg), the maximum plasma concentration was only 0.28 µM5. This is 18 times lower than the concentration required to reduce viral replication of SARS-CoV-2in vitro . Ivermectin accumulation in tissues is mild and would not be sufficient to achieve the antiviral effect with conventional doses6. Although high doses of ivermectin in adults or children are well tolerated5,7, the clinical effects of ivermectin at a concentration of 5 μM range are unknown and may be associated with toxicity. Consequently, ivermectin has in vitroactivity against SARS-CoV-2 but this effect is unlikely to be observedin vivo using current dosing.Amidst fear of the pandemic, the public and some physicians are now using ivermectin off-label for prophylaxis or as adjuvant therapy for COVID-19. Because ivermectin is only commercially available as a 3 or 6 mg tablets or a 6 mg/ml oral suspension, in order to administer a high dose, some people may experiment with more concentrated veterinary formulations. These actions are not based on clinical trials and have motivated cautionary statements from institutions such as the FDA against the use of pharmaceutical formulations of ivermectin intended for animals as therapeutics in humans 8.Potential avenues for further investigation into repurposing ivermectin for SARS-CoV-2 may be to: (i) develop an inhaled formulation to efficiently deliver a high local concentration in the lung, whilst minimizing systemic exposure; and (ii) evaluate more potent ivermectin analogs (e.g. doramectin) which may also inhibit SARS-CoV-2. These are areas for research – clearly, further studies are needed before ivermectin can be used for the prevention and treatment of COVID-19. As recently discussed in BJCP, this highlights the critical need to consider pharmacological principles to guide in vitro testing when repurposing old drugs for therapeutic use against COVID-199.

Xiao Zhu

and 3 more

A recent commentary published in BJCP used lopinavir/ritonavir as an example to highlight the importance of the clinical pharmacology principles in the repurposing of old drugs for therapeutic use against Coronavirus disease 19 (COVID-19).1 Here, we provide another example to support this point.A recent study found that ivermectin, an FDA-approved anti-parasitic drug, has inhibitory effects on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2 Ivermectin has broad anti-viral activity through inhibition of viral proteins including importin α/β1 heterodimer and integrase protein.3 In the in vitro study reported by Caly and colleagues, the addition of ivermectin at a concentration of 5 micromolar (μM) (twice the reported IC50) to Vero-hSLAM cells 2 hours post infection of with SARS-CoV-2 resulted in a reduction in the viral RNA load by 99.98% at 48 hours.2Large trials of mass drug administration of ivermectin in adults and children have shown that ivermectin is well tolerated.4 Even at doses that are 10 times greater than the highest FDA-approved dose of 200 μg/kg, central nervous system toxicity has not been reported.5 However, following the oral administration of supra-therapeutic doses of ivermectin (i.e. 120 mg) the maximum plasma concentration achieved was 0.28 ± 0.18 (standard deviation) μM, a value 18 times lower than the reported 5 μM ivermectin concentration used by Caly et al in their SARS-CoV-2 experiment.5 To date, the clinical effects of ivermectin at a concentration of 5 μM range are unknown, but likely to be toxic. Furthermore, ivermectin is only commercially available as a 3 mg oral tablet.6 These factors hinder our ability to immediately repurpose ivermectin in its current form for the treatment of COVID-19.While the findings by Caly and colleagues provide some promise, viral suppression was not seen at concentrations observed with standard doses in humans. Further preclinical in vivo studies should evaluate the pharmacokinetics and pharmacodynamics to determine the kill pattern of ivermectin. A potential alternate solution may be to develop an inhaled formulation of ivermectin to efficiently deliver a high local concentration in the lung, whilst minimising systemic toxicity. As therapeutic agents to tackle the COVID-19 pandemic are urgently sought, careful consideration of the pharmacokinetics of these drugs should be considered to guide in vitro testing.