Additional clinical data
In addition to data used for model validation, additional data were used to get some insight on dose-exposure-response as regards clinically relevant beneficial and toxic effects of HCQ in COVID-19. Even though these data could not permit a formal exposure-response analysis, they were used to describe the doses and PK exposure distributions in COVID-19 patients either with favourable responses (discharge from the hospital based on criteria described below) or experiencing adverse drug reactions after treatment with HCQ. Summary level and patient level data were used for this purpose.
Summary level data
These include data from 3 previously published clinical data in COVID-19 patients treated either with HCQ monotherapy [8-9] or with HCQ combined with azithromycin (AZM) [7, 10].
Patient level data
Clinical data were obtained from 172 COVID-19 in-patients hospitalised at Saint-Pierre Hospital in Brussels (Belgium) from 1st of March to 6th of April 2020 and treated with HCQ monotherapy. Summary of patient characteristics as well as relevant information available on their disease stage and response to HCQ monotherapy are included in Table 2. Statistical analysis was performed using SAS JMP v.10 software. Criteria for hospitalization included COVID-19 suspicion based on radiological findings in patients with known severity factors (hypertension, diabetes, lung disease, age >60) and/or with one the following criteria oxygen desaturation <94% while breathing ambient air, respiratory rate > 22/min, heart rate >125, decrease of oxygen saturation <94% after one minute walking test altered consciousness; The following criteria were taken into account before discharge: no requirement of oxygen supplementation, no evidence of desaturation while walking without oxygen supplementation, ability of oral medication intake and appropriate condition for isolation at home.
Moreover, EudraVigilance (EV), an European public vigilance database including spontaneous reports of adverse events with medications, was consulted and cases related to the use of HCQ in COVID-19 extracted.