Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties

Abstract

Since in vitro studies and a preliminary clinical report suggested the efficacy of chloroquine for COVID-19-associated pneumonia, there is increasing interest in this old antimalarial drug. In this article, we discuss the pharmacokinetics and safety of chloroquine that should be considered in light of use in SARS-CoV-2 infections. Chloroquine is well absorbed and distributes extensively resulting in a large volume of distribution with an apparent and terminal half-life of 1.6 days and 2 weeks, respectively. Chloroquine is metabolized by cytochrome P450 and renal clearance is responsible for one third of total clearance. The lack of reliable information on target concentrations or doses for COVID-19 implies that for both adults and children, doses that proved effective and safe in malaria should be considered, such as 'loading doses' in adults (30 mg/kg over 48 h) and children (70 mg/kg over 5 days), which reported good tolerability. Here, plasma concentrations were < 2.5 μmol/L, which is associated with (minor) toxicity. While the influence of renal dysfunction, critical illness, or obesity seems small, in critically ill patients, reduced absorption may be anticipated. Clinical experience has shown that chloroquine has a narrow safety margin, as three times the adult therapeutic dosage for malaria can be lethal when given as a single dose. Although infrequent, poisoning in children is extremely dangerous where one to two tablets can potentially be fatal. In conclusion, the pharmacokinetic and safety properties of chloroquine suggest that chloroquine can be used safely for an acute virus infection, under corrected QT monitoring, but also that the safety margin is small, particularly in children.

Fig. 1

Plasma concentration–time profile in a typical adult patient of 50 kg with normal renal function (dotted line), 70 kg with renal impairment (25% reduction in clearance [CL], short dashed line), 70 kg with normal renal function (solid line), and in an obese adult of 150 kg with normal renal function (long dashed line) based on the pharmacokinetic model from Zhao et al. [20], which was adapted for obese patients (i.e., 0.75 allometric increase in CL and maximized volumes and intercompartmental CL on values for an 80-kg individual; see ESM for details). Two dose regimens were simulated: a dose regimen according to the SWAB (Dutch Working Party on Antibiotic Policy) guideline [69] (total 3300 mg over 5 days with 600 and 300 mg on the first day) and b dose regimen according to Pussard et al. [47] (30 mg/kg over 48 h with a maximum dose of 2400 mg [80 kg] for obese patients). Chloroquine concentrations are shown in μmol/L (left axis) and mcg/L (right axis). To compare plasma concentrations with whole blood concentrations, multiply by a factor of 2.5–8 [1, 16, 17]. WT body weight

Fig. 2

Plasma concentration–time profile in four typical children of 0.5, 2, 4, and 8 years of age with normal renal function (solid line) or with renal impairment (25% reduction in clearance [CL], dashed line) based on the pharmacokinetic model from Zhao et al. [20], which was adapted for children aged below 5 and 1 years to be in agreement with observations in children in other reports [19, 50, 51] (i.e., a reduction in CL to 75% and 50% on top of allometric scaling (that is already in the model) for children below 5 and 1 year of age, respectively (see ESM for details). Two dose regimens were simulated: a dose regimen according to the SWAB (Dutch Working Party on Antibiotic Policy) guideline/Dutch Children’s Formulary [69] (total 55 mg/kg over 5 days) and b dose regimen according to Ursing et al. [19] (70 mg/kg over 5 days). Chloroquine concentrations are shown in μmol/L (left axis) and μg/L (right axis). To compare plasma concentrations with whole blood concentrations, multiply by a factor of 2.5–8 [1, 16, 17]