COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

Abstract

• Chloroquine and hydroxychloroquine have been used for over 60 years in the treatment of malaria, amoebic liver abscess, and several rheumatological conditions, but their clinical pharmacology is not well understood. COVID-19 is a new potential indication, although these drugs have only moderate in vitro activity against the SARS-CoV-2 virus and there is no convincing evidence at this time of significant clinical efficacy. • Chloroquine and hydroxychloroquine both have unusual pharmacokinetic properties with enormous apparent volumes of distribution (chloroquine > hydroxychloroquine) and very slow elimination from the body (terminal elimination half-lives > 1 month). • The free plasma concentrations that drive potentially serious adverse reactions (hypotension, cardiac conduction disturbances, delayed ventricular repolarization, and neurotoxicity) are determined largely by distribution processes. • Hydroxychloroquine was slightly safer than chloroquine in preclinical testing and is considered better tolerated over the long term. Both drugs are dangerous when overdosed, and parenteral administration needs careful control. • There are different salts, each with a different base equivalent. This has led to confusion and sometimes mistakes in dosing. As different salts are available in different places, malaria treatment is usually recommended in terms of base equivalent. Tablets of the two most widely available forms, chloroquine diphosphate 250 mg salt and hydroxychloroquine sulphate 200 mg salt, both contain 155 mg base. • The pro-arrhythmic and anti-arrhythmic effects of chloroquine and hydroxychloroquine have been poorly characterised, although the majority of evidence for current regimens is very reassuring. Arrhythmia risks have been inferred from QT prolongation rather than observed. • We used available pharmacokinetic information from healthy volunteers, the treatment of malaria, the chronic treatment of rheumatological conditions, and the toxicokinetics of chloroquine in self-poisoning to predict exposures and safety margins in the high-dose COVID-19 prevention and treatment regimens that have been evaluated. • These regimens are predicted to have reasonable safety margins. Using lower doses risks failing to identify any putative benefit in this potentially lethal infection. Dose regimens should aim to avoid reaching whole-blood concentrations over 10 μM (3.2 μg/mL), which correspond approximately to plasma concentrations >3 μM (1 μg/mL). • Large, well-conducted randomised clinical trials with appropriate monitoring are required to determine if chloroquine and hydroxychloroquine have preventive or treatment efficacy in COVID-19 and acceptable safety. Current recommendations for their use outside of clinical trials are not justified at this time.