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Prolonged dose interval of adalimumab safe for patients with RA

Audrey Abella
31 Jul 2018

Patients with rheumatoid arthritis (RA) who have received the monoclonal antibody adalimumab with serum trough concentrations above 8 μg/mL may safely prolong their dosing interval to once every 3 weeks without loss of disease control, according to a Dutch study.

Of the 147 patients screened, 55 with adalimumab trough concentrations of >8 μg/mL were randomized 1:1 to either dose-interval prolongation of once every 3 weeks or continuation of the standard interval of every other week for 28 weeks. [Ann Rheum Dis 2018;77:484-487]

At week 28, mean adalimumab concentration in both prolongation and continuation arms decreased (from 10.6 μg/mL to 6.6 μg/mL and from 10.4 μg/mL to 9.3 μg/mL, respectively). Mean between-group difference was 2.6 μg/mL (95 percent confidence interval [CI], 1.2–4.1; p=0.001).

Adalimumab concentration in 73 percent of patients remained above 5 μg/mL. Participants whose adalimumab concentration fell below 5 μg/mL had no clinical consequences in the 28 weeks thereafter, noted the researchers.

Considering mean change in disease activity, the prolongation arm did well, demonstrating minimal improvement vs those in the continuation arm at week 28 (mean ΔDAS28*, -0.14 vs 0.30), with a mean difference that significantly favoured the prolongation arm (0.44, 95 percent CI, 0.76 to -0.12; p=0.01).

After week 28, an increase in DAS28 of ≥0.6 points was observed in both prolongation and continuation arms (26 percent and 37 percent; p=0.56). The observed increase in the continuation arm was attributed to the natural fluctuation in DAS28 during standard-dose treatment. [Arthritis Care Res 2013;65:1608-1616]

Although higher adalimumab concentrations result in better clinical response, the curve plateaus around 5 μg/mL, which has been reported to be the necessary concentration to block TNF**. [Ann Rheum Dis 2015;74:513-518] Therefore, patients with steady-state trough concentrations above 5 μg/mL are most likely overexposed, said the researchers.

“Overexposure as a result of high adalimumab concentrations is independent of disease activity since the cut-off of 5 μg/mL is observed in patients with active disease,” said the researchers. “For many patients in remission, concentrations lower than 5 μg/mL might be sufficient to remain in that state.”

The findings address the issue of overexposure and underscores the potential benefit of therapeutic drug monitoring, which is important in view of factors such as drug costs – which may be reduced by 33 percent – and the possible risk of adverse events. [JAMA 2006;296:2201-2285; Arthritis Rheumatol 2017;69:108-113]

“[Overall, our findings show that] patients with adalimumab concentrations >8 μg/mL can prolong their dosing interval by 50 percent without a clinically relevant change in disease activity,” said the researchers.

However, the researchers noted that the treatment duration might have limited the findings, as median treatment duration with adalimumab is 5.5 years, which is significantly longer than the study requirement of 28 weeks.

Another potential limitation is the study population, which primarily included patients with minimal disease activity or those in remission, noted the researchers. “[A] proportion of these patients could prolong the dosing interval even further.”

Moreover, some patients reverted to standard dosing despite the lack of significant change in DAS28, they added. “Although DAS28 may be insensitive to relevant changes in the low disease activity range, we saw similar effects in [simplified and clinical disease activity scores] … More sensitive outcomes might be necessary in future studies to detect flares.”

 

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Pearl Toh, 07 Aug 2018
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