Determinants of Hydroxychloroquine Blood Concentration Variations in Systemic Lupus Erythematosus

Abstract

Objective Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. Methods We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded. Results To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug–drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute [range 23–58 ml/minute]) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml [range 504–2,229 ng/ml] versus 917 ng/ml [range 208–3316 ng/ml]) (P < 0.001). Conclusion We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians.

Hydroxychloroquine dosing in immune-mediated diseases: implications for patient safety

“…For example, clinicians may intentionally prescribe doses above recommendations to better manage a patient’s disease, and lowering HCQ dose in certain individuals has the potential to increase symptoms and disease activity [18, 19]. There is also concern that lowering dosage may cause patients to fall out of therapeutic range of HCQ, as various factors have been associated with blood concentration of HCQ, such as renal insufficiency, high estimated creatinine clearance, and disease activity [20, 21]. Since the newer recommendation is based on one retrospective case-control study of patients within Kaiser Permanente [4], additional, prospective studies are needed to assess whether the 5.0 mg/kg threshold significantly reduces risk of retinal toxicity in other populations.…”

A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self‐Administered Questionnaires

“…Although the large French multicenter randomized prospective study PLUS did not confirm the interest of adapting daily HCQ dosage to its blood level in terms of efficacy, it did confirm the correlation between HCQ levels and efficacy . Possibly most important, since the blood half‐life of HCQ is at least 5 days, and the terminal half‐life of HCQ is 43 days, very low blood HCQ levels objectively indicate severe nonadherence (i.e., identify patients who have not taken HCQ for a significant period and not those who miss a few tablets) …”

Routine Hydroxychloroquine Blood Concentration Measurement in Systemic Lupus Erythematosus Reaches Adulthood

“…By contrast, the mean elimination half-life of HCQ was 123 ± 45 h in another study 5 . Accordingly, we have shown that some patients may reach high levels of [HCQ] within only a few days 9 , showing that while specific, low [HCQ] are probably not highly sensitive to diagnose nonadherence, and that even if rates of nonadherence as high as 29% have been found in patients with SLE, this is likely only the "tip of the iceberg." (3) The respective importance of measurement of HCQ versus its metabolites has not been fully addressed.…”

“…(1) The determinants of variations of [HCQ] are not fully understood 9 . (2) Even if it is written almost everywhere that HCQ half-life is around 40 days, this value refers to the terminal half-life.…”