Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials

OBJECTIVE: To characterize hydroxychloroquine exposure in patients with rheumatic disease receiving long-term hydroxychloroquine compared to target concentrations with reported antiviral activity against the 2019 coronavirus SARS-CoV-2. METHODS: We evaluated total hydroxychloroquine concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric lupus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted hydroxychloroquine concentrations to target concentrations with reported antiviral activity against SARS-CoV-2. RESULTS: The average total serum/plasma hydroxychloroquine concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/L in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/L), all studies had approximately one-tenth the necessary concentration for in-vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose. CONCLUSION: We found that the average patient receiving treatment with hydroxychloroquine for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in-vitro. Nevertheless, patients receiving hydroxychloroquine long-term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for hydroxychloroquine in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for hydroxychloroquine.