Nicholas J. White, James A. Watson, Richard M. Hoglund, Xin Hui S. Chan, Phaik Yeong Cheah, Joel Tarning
Introduction
Chloroquine [7-chloro-4-[4-(diethylamino)-1-methylbutyl]amino] quinoline is a 4-aminoquinoline compound discovered in Germany in 1934 as part of a research programme to develop new antimalarial drugs [1, 2]. Hydroxychloroquine, in which one of the ethyl groups in the alkyl side chain is hydroxylated, was synthesized in 1946 (Fig 1). Early clinical pharmacology assessments in the United States of America characterised the safety, tolerability, and antimalarial efficacy of chloroquine. By the early 1950s, chloroquine had become the treatment of choice for all malaria throughout the world, and hundreds of metric tonnes (corresponding to nearly 100 million malaria treatment doses) were dispensed annually [3]. Industrial production peaked in 2004. In the last quarter of 2004, China alone reported production of over 400 tonnes [4]. Thus, well over 5 billion treatments have been dispensed worldwide. Chloroquine can claim to be among the drugs to which humans have been most exposed.
Discussion
Despite the enormous usage of chloroquine in malaria and hydroxychloroquine in rheumatological conditions for over half a century, their clinical pharmacology is not well understood. There are several confusing aspects to their pharmacological assessment. First, dosing is sometimes reported as base equivalent (usually in malaria) and sometimes as salt (rheumatological conditions). Of the 49 different chloroquine or hydroxychloroquine treatment regimens under evaluation for COVID-19 (on clinicaltrials.gov; accessed May 20, 2020), only six explicitly mention the base equivalent. Second, the measurement of these drugs in plasma and blood samples is complicated by extensive binding to platelets, leukocytes, and to a lesser extent, erythrocytes (and in malaria, concentration within malaria parasites). Third, they have complex pharmacokinetic properties characterised by an enormous total apparent volume of distribution and very slow terminal elimination such that blood concentration profiles in acute illness are determined by distribution rather than elimination. Finally, there are still considerable uncertainties about their mode of action.
Acknowledgments
We thank Jean-Luc Clemessy and Frederic Baud for providing us with the original data from the chloroquine self-poisoning studies.
Citation: White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J (2020) COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med 17(9): e1003252. https://doi.org/10.1371/journal.pmed.1003252
Published: September 3, 2020
Copyright: © 2020 White et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received no specific funding for this work.
Competing interests: NJW is a member of the PLoS Medicine Editorial Board. The authors declare that no other competing interests exist.
Abbreviations: ARDS, acute respiratory distress syndrome; CalHR, calibrated hazard ratio; CI, confidence interval; DMC, data monitoring committee; ECG, electrocardiograph; FDA, US Food and Drug Administration; G6PD, glucose-6-phosphate dehydrogenase; HPLC, high-performance liquid chromatography; MATE1, multidrug and toxin extrusion protein 1; MHRA, Medicines and Healthcare products Regulatory Agency (UK); MS/MS, tandem mass spectrometry; P-gp, P-glycoprotein; RCT, randomised controlled trial; SLE, systemic lupus erythematosus; TdP, torsade de pointes; WHO, World Health Organization
