Background Several studies show correlation between trough serum concentrations of TNF-alpha inhibitors and treatment efficacy (1,2). In spite of this, patients are treated with standard dosages as in “one size fits all”. Individualised treatment based on trough value of etanercept might optimise treatment and reduce risk of adverse events. However, the time window to determine the trough value of etanercept in patients on standard dosing is not known. Based on the pharmacokinetics of etanercept (t_max approx. 69 h, t_1/2 approx. 102 h) the purpose of this study was to challenge the window to determine trough values in patients treated with etanercept with and without concomitant methotrexate.

Objectives To explore the time window to determine trough values of etanercept and whether concomitant treatment with methotrexate influence the width of the window.

Methods Six arthritis patients with concomitant methotrexate and six arthritis patients without were included. Serum concentrations of etanercept were measured before dosing, at day 3 (t_max), at day 6, and before next dosing at day 7 thus focusing on trough rather than peak values. Serum concentrations of etanercept were assessed by ELISA technique (3).

Results The study included 12 female patients (10 diagnosed with rheumatoid arthritis and 2 with juvenile arthritis equally distributed between groups) treated with etanercept, with or without concomitant methotrexate. In the methotrexate group the average dosage was 15.4 mg/week (SD=6.4). For the whole study population, the age was 59.5 years (SD=15.4) with disease duration of 23.5 years (SD=7.4), and an average DAS28CRP of 2.2 (SD=0.6). There were no differences between the two subgroups in regard to age, disease duration, and years of treatment with etanercept, while the group treated without methotrexate tended to have a lower DAS28CRP (1.9 vs 2.5, p=0.06).

In a mixed-effect logistic regression model, methotrexate did not influence the serum levels of etanercept (P=0.6).

As expected there was a significant increase in serum level of etanercept on day 3 (t_max), while no difference was seen between day 0 and day 6 or 7 (compatible with the t½ of approx. 4 days), thus allowing considering extension of the window to determine trough values. However, a post hoc analysis confirmed a decline in concentrations from day 6 to day 7 of 0.32 mg/l (SD=0.29). In light of the rather narrow concentration ranges found in patient populations (1,2) it can not be ruled out as clinical irrelevant.

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Conclusions Concomitant methotrexate did not influence the serum levels of etanercept.

The day to day decrease in serum concentrations of etanercept at the end of a dosing interval must be considered when designing an algorithm for serum-concentration based personalized medicine.

1. Jamnitski A et al. Ann Rheum Dis. 2012; 71:88–91.

2. Kneepkens EL, et al. Ann Rheum Dis 2015;74: 1825–1829

3. Vries et al, Ann Rheum Dis 2009;68:531–535

Disclosure of Interest None declared