Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19

Noël Zahr, Saik Urien, Benoit Llopis, Valérie Pourcher, Olivier Paccoud, Alexandre Bleibtreu, Julien Mayaux, Estelle Gandjbakhch, Guillaume Hekimian, Alain Combes, Olivier Benveniste, David Saadoun, Yves Allenbach, Bruno Pinna, Patrice Cacoub, Christian Funck-Brentano, Joe-Elie Salem, Noël Zahr, Saik Urien, Benoit Llopis, Valérie Pourcher, Olivier Paccoud, Alexandre Bleibtreu, Julien Mayaux, Estelle Gandjbakhch, Guillaume Hekimian, Alain Combes, Olivier Benveniste, David Saadoun, Yves Allenbach, Bruno Pinna, Patrice Cacoub, Christian Funck-Brentano, Joe-Elie Salem

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.

Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Figures

Figure 1
Figure 1
Observed blood (red) and plasma (green) hydroxychloroquine concentrations. Numbers stand for the patient identity and lines for the corresponding spline describing the overall trend for each matrix.
Figure 2
Figure 2
Prediction-corrected visual predictive check for plasma (A) and blood (B) hydroxychloroquine population pharmacokinetics. Plain () and green lines stand for prediction-corrected observed concentrations and their 5th, 50th and 95th percentiles. Light blue and red bands stand for the corresponding model-predicted 90% confidence intervals.
Figure 3
Figure 3
Representative predicted plasma hydroxychloroquine (HCQ) concentrations-time courses as a function of the dosing regimen evaluated in major prospective trials testing HCQ for COVID-19. Curves are drawn according to our final parameters for a typical patient weight (WT) of 79 kg (observed median). Dosing schedules are 2.4 g loading dose then 400 mg/12 h (RECOVERY), 1.2 g loading dose then 200 mg/8 h (SANOFI), 200 mg/8 h (IHU Marseille) and 800 mg loading dose then 400 mg/24 h (DISCOVERY). Curves shown are using COVID-19 patients (A), lupus patients (B), malaria patients (C), and healthy subjects (D) parameters.
Figure 4
Figure 4
Possible dosing regimen in COVID-19 patients (weighing 79 kg) according to our final model. Dosing schedules represented are 800 mg/12 h (total 1600 mg) the 1st day, then 400 mg/12 h (RED); 800 mg/12 h (total 1600 mg) the 1st day, then 200 mg/8 h (ORANGE); 400 mg/8 h (total 1200 mg) loading dose the 1st day, then 400 mg/12 h (BLUE); 600 mg/8 h (total 1800 mg) loading dose the 1st day, then 200 mg/8 h (GREEN).
Figure 5
Figure 5
Mean plasma hydroxychloroquine (HCQ) concentration-time courses for a patient with bodyweight (WT) 103 kg and half-life >70 h, red and blue curves, respectively (A) and for typical patients with 79 kg WT and clearance (CL) ranging between 30–68 L/h and volume of distribution (Vd) between 4765–13,470 L, black curves drawn from variable CL and Vd Bayesian estimates (B). Dosing regimen is 200 mg HCQ/8 h, with no loading dose.
Figure 6
Figure 6
Time-to-Sars-Cov-2 PCR negativation curves as a function of hydroxychloroquine (HCQ) plasma levels within 48 hours of HCQ start. Blue and red curves represent patients with an HCQ plasma concentration at 48 h below or above the 1st HCQ plasma concentration quartile observed in our cohort, respectively (72 ng/mL, A), median (95 ng/mL, B) and 3rd quartile (129 ng/mL, C).

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