Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options

McCreary, Erin K; Pogue, Jason M

To inform optimal dosing of hydroxychloroquine, the investigators then performed PBPK modeling. In this analysis, the investigators utilized human population pharmacokinetic and rat lung penetration data for each compound to estimate free trough concentrations in the lung to EC 50 ratios (R LTEC ) [18] . Because 500 mg of chloroquine by mouth twice daily has been reported to demonstrate efficacy against SARS-CoV-2, the target R LTEC for hydroxychloroquine regimens was set to ≥2.38 (day 1), 5.92 (day 3), and 18.9 (day 5), which were the R LTEC values predicted with the "efficacious" 500 mg by mouth twicedaily dosing of chloroquine [16] . Various dosing regimens were simulated, but 2 are particularly notable. The first was an oral loading dose of 1200 mg (divided 800 mg then 400 mg) on day 1, followed by 400 mg daily. This regimen led to significantly higher R LTEC on day 1 (33.3), day 3 (55.1), and day 5 (103) than those values demonstrated with chloroquine. The second regimen was a loading dose of 800 mg (400 mg × 2) on day 1 followed by 200 mg twice daily. This was also associated with higher R LTEC values than chloroquine on day 1, 3, and 5 (corresponding to 21.0, 38.9, and 85.4, respectively) [18] . The authors concluded that these data support the lower dose regimen because R LTEC values were significantly higher than those with the "proven efficacious" regimen of 500 mg of chloroquine by mouth twice daily. Clinicians should note that both chloroquine and hydroxychloroquine have half-lives of ~40 days [19] , and therefore short durations would likely provide prolonged courses of therapy. This was exemplified in the PBPK modeling in which R LTEC values with hydroxychloroquine were predicted to still be above the targeted efficacy threshold on day 10, even with a 5-day course of therapy.