3 Results

The popPK model by Carmichael et al was successfully replicated as shown in Figure 1. Results of external validation were satisfactory: the model by Carmichael was able to acceptably predict previously published data from external sources in CLE and in COVID-19 patients (see Figure 1).
This model was therefore used to simulated different dosing scenarios including in national guidelines and ongoing/planned clinical study protocols in Belgium. Results of the different simulations are shown in Figure 2.
Selected clinical response markers including time to discharge from the hospital, survival, C-reactive protein, blood oxygen levels and absolute lymphocyte counts were collected from a cohort of 172 patients treated with HCQ monotherapy at Saint Pierre Hospital in Brussels. Summary descriptive statistics are included in Table2 together with patient age and relevant comorbidities. Most of these patients received 5 day treatment scheme with 400mg BID on day 1 followed by 200mg BID from days 2 to 5. Three patients received 6 or 7 days of treatment. As regards impact of HCQ treatment on CRP, blood oxygen levels and absolute lymphocyte counts, while all the patients received the same dosing regimen for HCQ, variable responses were observed for each of the biomarkers: a subset had their levels decreasing (i.e. negative slope) after start of treatment with HCQ, while others had an increase of the levels (positive slope). Moreover, time delay from apparition of symptoms to implementation of treatment was a significant predictor of admission to the intensive care unit (p<0.01, AUC ROC curve= 0.63) and death (p<0.01, AUC ROC curve= 0.61) based on logistic regression analysis, while patient age, hypertension, cardiomyopathies, cancer and obesity were significantly correlated with patient death (p<0.05).
As regards clinical safety, case reports were found from literature data and public vigilance database (EV). The dosing regimens information were extracted when provided in the report and in most of the cases 800 mg daily or lower doses were reported for day 1 and 400-600 mg daily were reported for the following days. The time delay from start of treatment to onset of ADR was very variable (from 1 to several days). Cardiac disorders and especially QT prolongation were the most frequently reported adverse drug reaction. At least one of the following additional risk factors were reported in patients experiencing adverse drug reactions: concomitant medication with at least one drug known to carry QT prolonging drugs or cardiac toxicity, relevant comorbidities (e.g. renal impairment), cardiovascular disease, cardiomyopathies and hypokalaemia (see Table 2).