Hydroxychloroquine in Coronavirus Disease 2019 Patients: What Still Needs to Be Known About the Kinetics

Martin‐Blondel, Guillaume; Ruiz, Stéphanie; Murris, Marlène; Faguer, S.; Duhalde, V.; Eyvrard, Frédéric; Izopet, Jacques; Mansuy, Jean‐Michel; Rolland, Yves; Delavigne, K.; Guimbaud, Rosine; Pugnet, G.; Conil, Jean‐Marie; Georges, Bernard; Delobel, Pierre; Minville, Vincent; Sifontes, Stein Silva; Concordet, Didier; Gandia, Peggy

doi:10.1093/cid/ciaa558

Cited by 11 publications

(14 citation statements)

References 12 publications

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“…The median HCQ concentrations observed in our study (i.e., 171 ng/ml; IQR, 128 to 207) are comparable to those reported in another study with COVID-19 patients (220 Ϯ 110 ng/ml) (35) and to steady-state trough levels observed in patients with systemic lupus erythematosus (i.e., 103 to 130 ng/ml) (36). Thus, the HCQ plasma concentrations in COVID-19 patients, in contrast to reported LPV plasma concentrations, were not higher than those previously observed in studies with other indications.…”

Section: Discussionsupporting

confidence: 88%

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Marzolini

Stader

Stoeckle

et al. 2020

Antimicrob Agents Chemother

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Background: Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP). Methods: LPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. Results: The median age of study participants was 59 (range 24–85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4–10) and 8 days (IQR 5–10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/mL (IQR 18.9–31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p<0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values. Conclusions: High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.

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Section: Discussionsupporting

confidence: 88%

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Marzolini

Stader

Stoeckle

et al. 2020

Antimicrob Agents Chemother

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“…The safety profile of HCQ is considered relatively good at the approved dose in inflammatory diseases. However, some recent data have also suggested that the safety of HCQ in COVID-19 patients might be different from the inflammatory diseases [ 18 ] There is currently a need for the characterization of HCQ safety, and in particular cardiac safety, in COVID-19 patients. [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…There is an urgent need for HCQ pharmacokinetic characterization in COVID-19, as acknowledged in recent publications. [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…[ 2 , 3 ] Four additional models describe plasma concentrations or merged blood and plasma concentrations [ 1 , 3 , 21 , 22 ] in healthy volunteers and patients. These models have been used to simulate COVID-19 patient exposures at different doses in a recent publication, under the unverified assumption that the pharmacokinetics of HCQ would be similar in other diseases and in COVID-19 (see, e.g., [ 18 , 23 ]).…”

Section: Introductionmentioning

confidence: 99%

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Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization

Thémans

Belkhir

Dauby

et al. 2020

Eur J Drug Metab Pharmacokinet

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Background and Objective In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. Methods We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. Results The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. Conclusion The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19. Electronic supplementary material The online version of this article (10.1007/s13318-020-00648-y) contains supplementary material, which is available to authorized users.

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“…In this issue of Clinical Infectious Diseases, Perinel et al and Martin-Blondel et al present results of pharmacokinetic studies of HCQ with the intent of informing optimal dosing strategies for COVID-19 [5,6]. Their intentions were sound.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Dose Optimization of Hydroxychloroquine for Coronavirus Infection 2019: Do Blood Concentrations Matter?

Ippolito

Flexner

2020

Clinical Infectious Diseases

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Hydroxychloroquine in Coronavirus Disease 2019 Patients: What Still Needs to Be Known About the Kinetics

Cited by 11 publications

References 12 publications

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization

Dose Optimization of Hydroxychloroquine for Coronavirus Infection 2019: Do Blood Concentrations Matter?

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