Commentary by Dr. Craig Rayner and Dr. Karen Yeo
Recently in Antiviral research, Caly et al.(1) reported the in vitro activity of ivermectin against SARS-CoV-2 in SERO cells. The study, described the pharmacological plausibility for ivermectin having activity against SARS-CoV2. However, it did not talk about the translation of the concentrations in the in vitro system tested to the clinic. Based on published pk information at the typical single dose of 150ug/kg plasma Cmax values would be at least 41-58 fold below the in vitro EC50 of 2.5 umol/L.
Using PBPK modelling, we showed that even a VERY high dose ivermectin regimen of 600 µg/kg dose daily for 3 days – the in vitro IC50 is >21-fold higher than the HIGHEST anticipated lung tissue concentrations.
Unless new “evidence emerges” that suggests clinically relevant concentrations with an appropriate safety window can be achieved, – which is not the case currently – clinical investigations should not be advocated for or supported.
Our time and resources are very precious now, and we must apply our resources to those compounds most likely to succeed against COVID-19. The burden of proof for moving drugs to the clinic MUST include consideration of translational pharmacology principles. If we don’t – we just move the risk forward to patients.
Science is littered with in vitro promise and clinical failure. That is not new. Read our letter to the editor HERE.
This is a good example of where a key method in the translational pharmacology tool box of PBPK can be applied.