Pharmacokinetics and Pharmacological Properties of Chloroquine and Hydroxychloroquine in the Context of COVID‐19 Infection

Abstract

Chloroquine and hydroxychloroquine are quinoline derivatives used to treat malaria. To date, these medications are not approved for the treatment of viral infections, and there are no well‐controlled, prospective, randomized clinical studies or evidence to support their use in patients with coronavirus disease 2019 (COVID‐19). Nevertheless, chloroquine and hydroxychloroquine are being studied alone or in combination with other agents to assess their effectiveness in the treatment or prophylaxis for COVID‐19. The effective use of any medication involves an understanding of its pharmacokinetics, safety, and mechanism of action. This work provides basic clinical pharmacology information relevant for planning and initiating COVID‐19 clinical studies with chloroquine or hydroxychloroquine, summarizes safety data from healthy volunteer studies, and summarizes safety data from phase II and phase II/III clinical studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of azithromycin and chloroquine in combination. In addition, this work presents data describing the proposed mechanisms of action against the severe acute respiratory distress syndrome coronavirus–2 and summarizes clinical efficacy to date.

Hydroxychloroquine Increased Anxiety-Like Behaviors and Disrupted the Expression of Some Related Genes in the Mouse Brain

“…In this study, HCQ was administered by intraperitoneal (i.p.) injection because approximately 70∼80% of HCQ can be absorbed upon oral administration (Nicol et al, 2020); thus, there would not be a large difference in drug absorption when the drug is administered orally and by i.p. injection.…”

“…In addition to acting as an antimalaria drug, HCQ is an immunomodulator that exerts broad anti-inflammatory effects, including inhibition of antigen presentation to dendritic cells, reduced signaling of both B and T cells and reduced cytokine production in macrophages (Nicol et al, 2020;Nirk et al, 2020). Microglia, as macrophages that reside in the brain and play critical roles in neuronal functions, are also potential targets of HCQ (Van Gool et al, 2001).…”

Hydroxychloroquine increased psychiatric-like behaviors and disrupted the expression of related genes in the mouse brain

“…Two time points were examined in this study, i.e., 24 h and 10 days after administration, and animal tissues were extracted 24 h after the completion of all the behavioral tests; thus tissues were collected 4 and 14 days after administration. Previous studies have shown that HCQ persists for a long time in vivo, with a half-life of 10-20 days in humans (13); however in rats, 80% of HCQ is eliminated by the 8th day, and 90% is cleared after 15 days (16). The metabolic rate of mice is approximately twice that of rats and 12 times that of humans (23), indicating that the direct effect of HCQ in the lasting group (10 days after administration) was likely quite small.…”

“…In addition to acting as an antimalaria drug, HCQ is an immunomodulator that exerts broad anti-inflammatory effects, including inhibition of antigen presentation to dendritic cells, reduced signaling of both B and T cells and reduced cytokine production in macrophages (6,13). Microglia, as macrophages that reside in the brain and play critical roles in neuronal functions, are also potential targets of HCQ (14).…”

Summary of the clinical manifestations, infection mechanisms and current drug treatment of SARS-CoV-2 infection

“…To date, these medications are not suitable to treat viral infections and there is no evidence supported by wellcontrolled, prospective, randomized clinical studies that demonstrate the efficacy of their use in patients with COVID-19. Nevertheless, CQ and HCQ are being studied alone or in combination with other agents to assess their effectiveness in the treatment or prophylaxis for COVID-19 (Nicol et al, 2020). The two drugs showed positive in vitro and clinical antiviral activity against SARS-CoV-2 (Gautret et al, 2020;Yao et al, 2020), which suggests that CQ and HCQ can be potential treatments for COVID-19.…”