Abstract
Background: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients.
Methods: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2.
Results: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs).
Conclusion: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.
Keywords: COVID-19; Hydroxychloroquine; Pharmacodynamics; Pharmacokinetics.
【저자키워드】 COVID-19, Hydroxychloroquine, pharmacokinetics, Pharmacodynamics, 【초록키워드】 SARS-CoV-2, Inflammation, Hydroxychloroquine, C-reactive protein, pharmacokinetics, in vitro, hospitalized patients, reverse transcription-PCR, viral clearance, Bioavailability, intensive care units, Liquid chromatography, nasopharyngeal swabs, Patient, plasma, Pharmacodynamics, HCQ, Lupus, covariates, estimate, distribution, COVID-19 patients, half-life, pharmacokinetic, Concentration, Analysis, dose, COVID-19 patient, followed by, volume of distribution, Volume, plasma concentration, Non-COVID-19 patients, 95% confidence interval, dosage, Variability, severe COVID-19 patients, circulating, pharmacokinetic data, e parameters, daily dose, clearance, parameter, Administered, effective, SARS-CoV-2 viral, Loading doses, pharmacokinetic analysis, tested, performed, reported, inhibit, required, median, hospitalized patient, were measured, ranged, elimination half-life, severe COVID-19 patient, 【제목키워드】 Hydroxychloroquine, hospitalized patient, with COVID-19,