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Objective: Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients., Methods: We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses., Results: For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2-4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements., Conclusions: We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy., Competing Interests: Competing interests: SB receives support from the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, consulting for UCB and Rutgers University and serves on an NIH DSMB. KS is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, the American Heart Association COVID-19 Fund to Retain Clinical Scientists Award and the Duke REACH Equity Career Development Award. JLR has received grant support from Pfizer, Exagen, Immunovant, Astra-Zeneca and consulting fees from GlaxoSmithKline, Amgen, Aurinia, Immunovant, Janssen, Eli Lily and Ampel Biosolutions. AE has received grant support from Pfizer, Exagen, Immunovant and GlaxoSmithKline and consulting fees from Amgen. RES receives grant support from the Arthritis Foundation, the Childhood Arthritis and Rheumatology Research Alliance and the Rheumatology Research Foundation. MM is a consultant for Astra Zeneca. LC-S receives grant support through UCB and the arthritis foundation. TO is an employee of Exagen. MC has received grant support from Pfizer, Exagen, Immunovant and Astra-Zeneca and consulting fees from GlaxoSmithKline, Amgen and UCB. DW is an independent director for Simulations Plus. HCQ Blood concentrations for the validation cohort were measured and paid for by Exagen Diagnostics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)