A strategy to maintain hydroxychloroquine blood levels above 1,000 ng/mL in adult patients with systemic lupus erythematosus did not reduce the number of SLE flares during a 7-month follow-up period, results from a French study demonstrated.
"This study confirms the pharmacokinetic/pharmacodynamic relation for hydroxychloroquine (HCQ) in patients with SLE," investigators led by Prof. Nathalie Costedoat-Chalumeau reported in the November 2013 issue of Annals of the Rheumatic Diseases.
"Our results do not justify recommending a therapeutic adaptation of HCQ dose. However, we suggest that [HCQ] be measured to detect non-adherence, especially in patients with active disease, and to help patients with poor adherence reach [HCQ levels greater than or equal to] 1,000 ng/mL."
The purpose of the trial, known at the PLUS Study, was to determine the potential benefits of individualizing HCQ dosing schedules to reach a target of 1,000 ng/mL or greater and thereby decrease rates of SLE flare. It was carried out in 573 patients with SLE at 37 centers in France from June 2007 through August 2010.
Of the 573 patients, researchers randomized 171 to one of two treatment groups: 84 to no daily dose change (group A), and 87 to increased HCQ dose to achieve the target of 1,000 g/mL or greater (group B). The primary endpoint was the number of patients with flares during 7 months of follow-up (Ann. Rheum. Dis. 2013;72:1786-92).
At the time of randomization, the mean age of patients was 40 years, 87% were female, and their average HCQ dose was 400 mg/day. At 7 months of follow-up, the proportion of SLE flare rates was similar between the two groups (25% in group A vs. 27.6% in group B; P = .7). In a subset analysis of 57 patients from group A whose HCQ values were below 1,000 ng/mL after randomization and 39 patients from group B who maintained the therapeutic target dose of 1,000 ng/mL or higher after randomization, patients in group B tended to fewer flares compared with their counterparts in group A (20.5% vs. 35.1%, respectively; P = .12).
One reason that HCQ dosing above 1,000 ng/mL did not reduce the rate of SLE flares during the study period "may be that higher doses do not have an added therapeutic effect," the researchers speculated. "However, several factors may provide an alternative explanation of why our study did not provide its primary hypothesis." For one, the maintenance of HCQ above 1,000 ng/mL during the 7 months of follow up "was difficult to achieve." This could be explained by two factors, they continued. "The first is the pharmacokinetic variations of HCQ, but this explanation is unlikely because HCQ has a long terminal half-life and these patients were thought to be in a steady state. The second potential explanation might be adherence problems, even though known or suspected non-adherence was a major criterion for exclusion in our study. We found 10 patients with [HCQ] sufficiently low at inclusion to constitute an objective marker of lack of compliance."
The researchers acknowledged certain limitations of the study, including the potential for being underpowered (171 patients studied though the calculated sample size called for 200), and that the trend toward lower SLE flares in patients with higher HCQ "must be interpreted cautiously, since this analysis was not performed according to randomization group. The result might also be explained by better adherence to other medications, especially steroids."
The study was funded by a grant from the French PHRC 2005 Ministère de la Santé. Sanofi provided the HCQ and placebo tablets.