{"doi":"10.1093/cid/ciaa691","title":"Dose Optimization of Hydroxychloroquine for Coronavirus Infection 2019: Do Blood Concentrations Matter?","abstract":"(See the Major Article by Mehta et al on pages 2469–79, published in the 1 November 2020 issue.) Clinical trials of hydroxychloroquine (HCQ) for the treatment of coronavirus infection 2019 (COVID-19) are moving forward on the heels of conflicting, and sometimes controversial, observational studies out of China and France from the first months of the pandemic [1–3]. The most recent National Institutes of Health guidelines for COVID-19 state that current data are insufficient to recommend for or against the use of HCQ or its predecessor chloroquine (CQ) [4]. Given the extraordinary times, clinicians the world over may reach for either drug in desperation. In this issue of Clinical Infectious Diseases, Martin-Blondel et al and Perinel 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. For most drugs, the concentration–response relationship is more informative than the dose–response relationship. Unfortunately, as has historically been the case with pharmacologic studies of HCQ, the current studies are bedeviled by the drug’s extraordinary pharmacokinetics. HCQ concentrations differed between the 2 studies by 4- to 8-fold for the same dosing regimen. Across all regimens, Martin-Blondel et al reported concentrations in the 40–240 ng/mL range compared with 1000–2000 ng/mL in the study by Perinel and colleagues. Martin-Blondel et al used plasma for their pharmacokinetic assays, whereas Perinel et al appear to have used whole blood, though this is not explicitly stated. Interpretation is further confounded by the different dosing regimens used in different patients. In our 2018 article in this journal [7], we reported plasma concentrations of CQ, a structural analogue of HCQ with similar pharmacokinetics, measured by a validated liquid chromatography-tandem mass spectrometry assay, and concentrations were on the same order as those reported by Martin-Blondel et al [5]. In all 3 studies there was a broad range of concentrations, as is often reported for HCQ and related compounds. Different sampling matrices (plasma, whole blood) yield highly discrepant measurements of HCQ, and it is from this observation that we can begin to pull back the curtain on the idiosyncratic pharmacokinetics of HCQ that may consign the exercise at hand to uninterpretable outcomes. Applying pharmacokinetic methods to optimize drug dosing is the preferred approach for most drugs. The alternative approach, predating the advent of clinical pharmacokinetics in the 1960s, is allometric and empirical. HCQ was developed in this earlier era, although it was still recognized for its extensive and unequal distribution with affinity for pigmented tissues and, important to note, lysosomes and other intracellular spaces [8]. HCQ is one of a small number of drugs for which the overwhelming driver of its pharmacokinetics is volume of distribution (Vd) rather than clearance. The typical Vd for HCQ is thousands to tens of thousands of liters for an average adult [9]. This imparts a long terminal elimination half-life, measured in weeks to months, despite relatively efficient renal and hepatic clearance. After a single 200-mg dose, HCQ remains detectable in urine for up to 3 months [10]. CQ, whose systemic pharmacokinetics are essentially indistinguishable from those of HCQ, remains detectable up to 1 year after the last dose of a typical malaria prophylaxis regimen [11]. HCQ’s enormous Vd is also the basis, in part, for the large interindividual variability in plasma and blood concentrations seen in the current studies and consistent with previous reports. Perinel et al speculate, justifiably, that the pharmacokinetics might further be altered by the pathophysiology of COVID-19. Then there is the potential role of enantiomeric differences in tissue distribution and drug effect, seen in other indications [12]. It is no wonder HCQ and CQ have vexed generations of clinical","journal":"Clinical Infectious Diseases","year":2020,"id":111073,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9497,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":498021,"name":"Charles Flexner","orcid":"0000-0002-4495-5349","position":1,"is_corresponding":false},{"id":407218,"name":"Matthew M. Ippolito","orcid":"0000-0001-5615-6440","position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-18T23:13:01.914939Z","pmid":"32474576","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}