Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application

We develop a population pharmacokinetic model for hydroxychloroquine (HCQ) and three of its metabolites (desethylhydroxychloroquine, Des HCQ; desethylchloroquine, DesCQ; and didesethylchloroquine, didesCQ) in COVID-19 patients in order to determine whether a pharmacokinetic (PK)/pharmacodynamic (PD) relationship was present. The population PK of HCQ was described using non-linear mixed effects modelling. The duration of hospitalization, the number of deaths, and poor clinical outcomes (death, transfer to ICU, or hospitalization >= 10 d) were evaluated as PD parameters. From 100 hospitalized patients (age = 60.7 +/- 16 y), 333 BHCQ and M were available for analysis. The data for BHCQ were best described by a four-compartment model with a first-order input (KA) and a first-order output. For M, the better model of the data used one compartment for each metabolite with a first-order input from HCQ and a first-order output. The fraction of HCQ converted to the metabolites was 75%. A significant relationship was observed between the duration of hospitalization and BHCQ at 48 h (r(2) = 0.12; p = 0.0052) or 72 h (r(2) = 0.16; p = 0.0012). At 48 h or 72 h, 87% or 91% of patients vs. 63% or 62% had a duration < 25 d with a BHCQ higher or below 200 mu g/L, respectively. Clinical outcome was significantly related to BHCQ at 48 h (good outcome 369 +/- 181 mu g/L vs. poor 285 +/- 144 mu g/L; p = 0.0441) but not at 72 h (407 +/- 207 mu g/L vs. 311 +/- 174 mu g/L; p = 0.0502). The number of deaths was not significantly different according to the trough concentration (p = 0.972 and 0.836 for 48 h and 72 h, respectively).