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Towards an individualised target concentration of adalimumab in rheumatoid arthritis Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA), but the response is highly variable between patients. Good responders have significantly higher adalimumab serum concentrations than non-responders.1 In a recent issue of the Annals, Pouw et al2 have proposed a therapeutic cut-off concentration for adalimumab that is predictive of clinical response at a population level but, as for other TNF-α antagonists, no individualised target concentration has been defined to adjust the dose in RA.3 In a post hoc analysis we measured adalimumab concentrations in 127 samples from 30 patients with RA who received 40 mg adalimumab subcutaneously every other week.4 Concomitantly to blood sampling, disease activity score in 28 joints (DAS28) was recorded at baseline and at 6 weeks, 12 weeks, 24 weeks and 52 weeks after treatment initiation. Then, we studied the relationship between adalimumab concentration and DAS28 with a direct Emax inhibition pharmacokinetic-pharmacodynamic model, using Monolix V.3.1 (INRIA, Saclay, France). Emax models are often used to describe the concentration-response relationship, where the ‘quantity’ of response is monotonically related to drug concentration.5 With such a model, the relationship reaches an asymptote for high adalimumab concentrations when DAS28 reaches its minimal value. Estimated baseline DAS28 and adalimumab IC50, that is, adalimumab concentration leading to 50% decrease of baseline DAS28, were 5.7 (coefficient of variation=10%) and 11.8 mg/L (coefficient of variation=75%), respectively. Therefore, for a patient with a median baseline DAS28=5.7, with an adalimumab concentration of 11.8 mg/L, the baseline DAS28 would be decreased twofold (figure 1). The adalimumab target concentration necessary to achieve a decrease in DAS28 from baseline to 3.2, that is, low disease activity, was obtained with the estimated parameters of the Emax inhibition model as follows: Ctarget ¼ IC50 

DAS280  3:2 3:2

where Ctarget is the adalimumab concentration needed to achieve DAS28=3.2 and DAS280 the DAS28 at baseline. A graph

Figure 2 Adalimumab concentration needed to achieve low disease activity according to baseline DAS28. This graph provides an estimation of the target concentration (Ctarget) on the X axis by baseline DAS28 (DAS280) on the Y axis, in patients with an average adalimumab IC50 (solid line). The dotted lines delineate the 25% to 75% interval. For example, the Ctarget for a patient with a DAS280 of 6.45 is 12 mg/L (squares), the Ctarget for a patient with a DAS280 of 4.55 is 5 mg/L (dots). The same approach was used to achieve clinical remission, that is, DAS28

Towards an individualised target concentration of adalimumab in rheumatoid arthritis.

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