Simulation of Drug in the Lung Can Be Misleading

To the Editor—Clinical Infectious Diseases published a manuscript by Yao et al, who used commercially available software (Simcyp) to conduct a probability of target attainment (PTA) analysis of hydroxychloroquine (HCQ) treatment for COVID-19 [1, 2]. Yao et al conclude that a dosage regimen of oral HCQ provides sufficient lung exposure to exceed the effective concentration killing 50EC50), and thus the regimen should be effective in treating patients with coronavirus disease 2019 (COVID-19). This conclusion is not warranted from the data presented.Yao et al claim that a regimen of oral HCQ sulfate of 200 mg twice daily for 5 days with 2 loading doses of 400 mg on day 1 provides lung concentrations (trough concentration, lung, free) that exceed the EC50 of HCQ for COVID (6.14 μM and 0.72 μM) at 24 and 48 hours, respectively. We simulated the Yao regimen “F” using a slightly modified version of an HCQ model published by Collins et al that includes intracellular lysosomal binding [3]. We then digitized the Yao plots to obtain the minimum blood and lung concentrations as these data are not presented in tabular form in the manuscript. Yao reported the predicted lung-to-plasma ratio of HCQ was 400 to 1; using a blood-to-plasma ratio of 7.2, this is a lung-to-blood ratio of 56 to 1. This figure is misleading as our simulation demonstrates that 98Table 1). Our simulation also predicts lysosomal concentrations in the lung to be gt;20 000 μM for the majority of the 5-day dosage regimen and the 5-day postregimen period. The lack of lysosomal binding in a model used to predict the concentration profile of a drug known to be highly lysomotropic overestimates drug in the lung tissue, as a significant amount of the drug is sequestered in the lysosomes. Whether the drug in the lysosomes retains antiviral activity is unknown.